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Cammisa I, Rigante D, Cipolla C. A Theoretical Link Between the GH/IGF-1 Axis and Cytokine Family in Children: Current Knowledge and Future Perspectives. CHILDREN (BASEL, SWITZERLAND) 2025; 12:495. [PMID: 40310145 PMCID: PMC12026182 DOI: 10.3390/children12040495] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND/OBJECTIVES Growth in childhood and adolescence is influenced by a complex interaction of genetic, environmental, and hormonal factors, with growth hormone (GH) and insulin-like growth factor 1 (IGF-1) playing crucial roles in linear growth and development. However, chronic inflammation, often detected in situations like inflammatory bowel disease and juvenile idiopathic arthritis, can significantly disrupt the GH/IGF-1 axis, causing a relevant growth impairment. METHODS We conducted a retrospective review focusing on the role of cytokines in the GH-IGF-1 axis and growth. RESULTS Inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 have been shown to contribute to GH resistance through an array of mechanisms that involve the downregulation of GH receptors and alterations in IGF-1 metabolism. This disruption negatively impacts the growth plate, particularly by impairing chondrocyte proliferation and differentiation, which are essential for proper bone elongation. This review delves into the intricate relationship among growth, chronic inflammation, and GH-IGF-1 axis, emphasizing the contribution of inflammatory cytokines in modulating GH signaling. It also highlights how cytokines can interfere with the molecular pathways that regulate skeletal growth, ultimately leading to growth disturbances in children suffering from chronic inflammatory diseases. CONCLUSIONS The findings underscore the importance of controlling inflammation in affected individuals to mitigate its detrimental effects on growth and ensure that children may reach their growth full potential.
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Affiliation(s)
- Ignazio Cammisa
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
| | - Donato Rigante
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
- Department of Life Sciences and Public Health, Università Cattolica Sacro Cuore, 20123 Rome, Italy
| | - Clelia Cipolla
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
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Shojaei Jeshvaghani Z, Mijnders M, Muffels I, van Beekhuizen S, Kotlarz D, Lindemans CA, Koletzko S, Klein C, Mokry M, Nieuwenhuis E, Kuijk E. TTC7A missense variants in intestinal disease can be classified by molecular and cellular phenotypes. Hum Mol Genet 2025; 34:313-326. [PMID: 39675053 DOI: 10.1093/hmg/ddae185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 12/05/2024] [Indexed: 12/17/2024] Open
Abstract
Biallelic mutations in tetratricopeptide repeat domain 7A (TTC7A) give rise to intestinal and immune disorders. However, our understanding of the genotype-phenotype relationship is limited, because TTC7A variants are mostly compound heterozygous and the disease phenotypes are highly diverse. This study aims to clarify how different TTC7A variants impact the severity of intestinal epithelial disorders. We individually characterized the molecular and cellular consequences of 11 different TTC7A missense mutations in TTC7A knockout Caco-2 cells. We examined variant-specific RNA expression profiles, TTC7A protein abundance, and endoplasmic reticulum (ER) stress by using RNA sequencing and imaging flow cytometry. For six variants we detected no significant alterations on these assays, suggesting that protein function may not be severely compromised. However, for five variants we observed molecular phenotypes, with overlapping gene expression signatures between specific variants. Remarkably, the TTC7AE71K variant displayed a unique expression profile, along with reduced TTC7A RNA and protein expression, which set it apart from all other variants. The findings from this study offer a better understanding of the role of specific TTC7A variants in disease and provide a framework for the classification of the variants based on the severity of impact. We propose a classification system for TTC7A variants that could help diagnosis, guide future treatment decisions and may aid in developing effective molecular therapies for patients that carry specific TTC7A variants.
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Affiliation(s)
- Zahra Shojaei Jeshvaghani
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6 3584 EA Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
| | - Marjolein Mijnders
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6 3584 EA Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
| | - Irena Muffels
- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6 3584 EA Utrecht, The Netherlands
| | - Sander van Beekhuizen
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6 3584 EA Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
| | - Daniel Kotlarz
- Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstraße 4, 80337 Munich , Germany
| | - Caroline A Lindemans
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6 3584 EA Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Department of Stem Cell Transplantation, Princess Maximá Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, Netherlands
| | - Sibylle Koletzko
- Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstraße 4, 80337 Munich , Germany
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn 11-082, Poland
| | - Christoph Klein
- Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Lindwurmstraße 4, 80337 Munich , Germany
| | - Michal Mokry
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6 3584 EA Utrecht, The Netherlands
- Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, Netherlands
- Laboratory of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
| | - Edward Nieuwenhuis
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6 3584 EA Utrecht, The Netherlands
- Rare Disease Center, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
| | - Ewart Kuijk
- Division of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6 3584 EA Utrecht, The Netherlands
- Regenerative Medicine Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
- Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, Lundlaan 6 3584 EA Utrecht, The Netherlands
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Shentova R, Mihova A, Velikova T. Dietary Supplements as Concentrated Sources of Nutrients with a Nutritional or Physiological Effect for Children with Inflammatory Bowel Disease. GASTROENTEROLOGY INSIGHTS 2024; 15:647-660. [DOI: 10.3390/gastroent15030047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2024] Open
Abstract
The consequences of inflammatory bowel disease (IBD) in children are connected to possible detrimental impacts on growth, development, psychosocial function, and general well-being. Therefore, the primary management plan in pediatric IBD is to achieve the long-term control of intestinal inflammation while also monitoring potential disease complications and therapeutic adverse effects, where nutritional management is of utmost importance. This review explores the role of dietary supplements as concentrated sources of nutrients with nutritional and/or physiological effects on children with IBD. While dietary supplements are commonly used in pediatric IBD management, their efficacy and, for some of them, safety remain subjects of debate. We provide an overview of the types of dietary supplements available and their potential benefits and risks in pediatric IBD patients. Additionally, we discuss the evidence supporting the use of specific supplements, their mechanisms of action, and considerations for clinical practice. Understanding the role of dietary supplements in pediatric IBD management is crucial for optimizing patient care and outcomes.
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Affiliation(s)
- Rayna Shentova
- Medical Faculty, Medical University—Sofia, 15 Akad. Ivan Geshov Blvd., 1431 Sofia, Bulgaria
| | - Antoaneta Mihova
- Department of Immunology, SMDL Ramus, Blvd. Kap. Spisarevski 26, 1527 Sofia, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Tsvetelina Velikova
- Department of Immunology, SMDL Ramus, Blvd. Kap. Spisarevski 26, 1527 Sofia, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
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4
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Huang J, Walters TD. Growth Impairment in Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:151-172. [DOI: 10.1007/978-3-031-14744-9_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Jensen EA, Young JA, Kuhn J, Onusko M, Busken J, List EO, Kopchick JJ, Berryman DE. Growth hormone alters gross anatomy and morphology of the small and large intestines in age- and sex-dependent manners. Pituitary 2022; 25:116-130. [PMID: 34373994 PMCID: PMC8905484 DOI: 10.1007/s11102-021-01179-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/27/2021] [Indexed: 02/03/2023]
Abstract
PURPOSE Growth hormone (GH) has an important role in intestinal barrier function, and abnormalities in GH action have been associated with intestinal complications. Yet, the impact of altered GH on intestinal gross anatomy and morphology remains unclear. METHODS This study investigated the influence of GH signaling on gross anatomy, morphology, and fibrosis by characterizing the small and large intestines in male and female bovine growth hormone transgenic (bGH) mice and GH receptor gene-disrupted (GHR-/-) mice at multiple timepoints. RESULTS The length, weight, and circumference of the small and large intestines were increased in bGH mice and decreased in GHR-/- mice across all ages. Colon circumference was significantly increased in bGH mice in a sex-dependent manner while significantly decreased in male GHR-/- mice. Villus height, crypt depth, and muscle thickness of the small intestine were generally increased in bGH mice and decreased in GHR-/- mice compared to controls with age- and sex-dependent exceptions. Colonic crypt depth and muscle thickness in bGH and GHR-/- mice were significantly altered in an age- and sex-dependent manner. Fibrosis was increased in the small intestine of bGH males at 4 months of age, but no significant differences were seen between genotypes at other timepoints. CONCLUSION This study observed notable opposing findings in the intestinal phenotype between mouse lines with GH action positively associated with intestinal gross anatomy (i.e. length, weight, and circumference). Moreover, GH action appears to alter morphology of the small and large intestines in an age- and sex-dependent manner.
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Affiliation(s)
- Elizabeth A Jensen
- Translational Biomedical Sciences Program, Graduate College, Ohio University, Athens, OH, USA
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Jonathan A Young
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Jaycie Kuhn
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - Maria Onusko
- The Diabetes Institute, Ohio University, Parks Hall Suite 142, Athens, OH, USA
- College of Arts and Sciences, Ohio University, Athens, OH, USA
| | - Joshua Busken
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
| | - Edward O List
- Translational Biomedical Sciences Program, Graduate College, Ohio University, Athens, OH, USA
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- The Diabetes Institute, Ohio University, Parks Hall Suite 142, Athens, OH, USA
| | - John J Kopchick
- Translational Biomedical Sciences Program, Graduate College, Ohio University, Athens, OH, USA
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA
- The Diabetes Institute, Ohio University, Parks Hall Suite 142, Athens, OH, USA
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA
| | - Darlene E Berryman
- Translational Biomedical Sciences Program, Graduate College, Ohio University, Athens, OH, USA.
- Edison Biotechnology Institute, Ohio University, Athens, OH, USA.
- The Diabetes Institute, Ohio University, Parks Hall Suite 142, Athens, OH, USA.
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
- Office of Research and Grants, Heritage College of Osteopathic Medicine, Ohio University, Irvine Hall 220B, Athens, OH, 45701, USA.
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Chronic inflammation and the growth hormone/insulin-like growth factor-1 axis. Cent Eur J Immunol 2021; 45:469-475. [PMID: 33613096 PMCID: PMC7882400 DOI: 10.5114/ceji.2020.103422] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 11/06/2020] [Indexed: 12/18/2022] Open
Abstract
Interactions between growth hormone (GH), insulin-like growth factor-1 (IGF-1), and the immune system are complex, bidirectional, but not fully explained. Current reviews based on numerous studies have indicated that chronic inflammation could suppress the GH/IGF-1 axis via several mechanisms such as relative GH and/or IGF-1 insufficiency, peripheral resistance to GH and/or IGF-1 resulting from down-regulation of GH and IGF-1 receptors, disruption in the GH/IGF-1 signalling pathways, dysregulation of IGF binding proteins (IGFBPs), reduced IGF bioavailability, and modified gene regulation due to changes in the microRNA system. It is well-known that relationships between the immune system and the GH/IGF-1 axis are mutual and GH as well as IGF-1 could modulate inflammatory response and the activity of systemic inflammation. Available data indicate that the GH/IGF-1 axis exerts both pro-inflammatory and anti-inflammatory effects. Pro-inflammatory cytokines such as interleukin-6 (IL-6), tumour necrosis factor-a (TNF-α), and interleukin-1b (IL-b) are some of the most significant factors, besides malnutrition, chronic stress, and prolonged use of glucocorticoids, which impair the activity of the GH/IGF-1 axis, and consequently lead to growth retardation in children suffering from childhood-onset chronic inflammatory diseases. In this review, we discuss the mechanisms underlying the impact of chronic inflammation on the GH/IGF-1 axis and growth processes during childhood and adolescence, based on a number of experimental and human studies.
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Sheng X, Sun X, Li F, Wang J, Ma J. Linear growth failure induced by systemic inflammation inhibiting IGF-1/IGFBP axis in rats with asymptomatic colitis. BMC Gastroenterol 2019; 19:96. [PMID: 31221091 PMCID: PMC6585116 DOI: 10.1186/s12876-019-1023-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 06/13/2019] [Indexed: 01/17/2023] Open
Abstract
Background Children in poor areas show significant growth retardation that does not improve with an adequate supply of energy and nutrients, which may be related to asymptomatic intestinal infection caused by poor sanitation. Our objective was to explore the mechanism of intestinal inflammation inhibiting growth in the setting of asymptomatic colitis. Methods Forty-eight 3-week-old Wistar rats were randomly divided into three groups: the control group, colitis group (with asymptomatic colitis induced by 2.5% trinitrobenzenesulphonic acid) and pair-fed group (daily food intake matched to the pair in the colitis group). The linear growth was assessed, and the plasma levels of hormone and systemic cytokines were detected and compared by independent two-sample t-test or one-way ANOVA among groups. Results At d5, the increases in the body length of the control, colitis and pair-fed groups were 1.65 ± 0.34 cm, 1.10 ± 0.30 cm and 1.38 ± 0.26 cm, respectively, and the increase in the body length in the colitis group was significantly less than that in the control group (P < 0.05). There were significant differences in the levels of hormone and cytokines among three groups (P < 0.05). Compared with the control group, rats in the colitis group exhibited linear growth failure, as well as higher expression of calprotectin, tumour necrosis factor-α, interleukin-6 and insulin-like growth factor binding protein 2, lower insulin-like growth factor-1 and insulin-like growth factor binding protein 3, and lower expression of nuclear factor kappa B in hepatocytes. Conclusions In addition to undernutrition, the systemic inflammatory response caused by asymptomatic colitis may inhibit the linear growth of rats by its influence on the insulin-like growth factor/insulin-like growth factor binding protein axis. Electronic supplementary material The online version of this article (10.1186/s12876-019-1023-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaoyang Sheng
- Department of Children and Adolescents Health Care, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute for Pediatric Research, MOE-Shanghai Key Laboratory of Children's Environmental Health, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Xueqing Sun
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 280 S. South Chongqing Road, Shanghai, 200025, China
| | - Feng Li
- Department of Children and Adolescents Health Care, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute for Pediatric Research, MOE-Shanghai Key Laboratory of Children's Environmental Health, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Junli Wang
- Department of Children and Adolescents Health Care, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute for Pediatric Research, MOE-Shanghai Key Laboratory of Children's Environmental Health, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Jingqiu Ma
- Shanghai Institute for Pediatric Research, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China.
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Piao J, Xu CL, Piao JA, Cao M, Huang N, Jin M. Expression analysis of proteasome maturation protein ( POMP) gene in Liaoning Cashmere goat. Anim Biotechnol 2019; 31:324-334. [PMID: 30957645 DOI: 10.1080/10495398.2019.1596946] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Liaoning Cashmere goat is a precious genetic resource of China. To explore the relationship between POMP and cashmere growth, we analyzed the expression of POMP. POMP encodes a hudrophilic protein which is most closely related to bos. RT-PCR showed that POMP was expressed in skin, heart, liver, spleen, lung, and kidney tissues. Real-time PCR showed that the expression of POMP was more active in the secondary hair follicles than the primary hair follicles in anagen. In situ hybridization showed that POMP was obviously expressed in the Inner Root Sheath (IRS) but no expression in Outer Root. The treatment of fibroblasts with melatonin (MT), fibroblast growth factors 5 (FGF5) and insulin-like growth factors 1 (IGF-1) showed that MT/FGF5/IGF-1 much performance for inhibiting the expression of POMP; MT + FGF5 inhibited the expression of POMP; MT + IGF-1 promoted the expression of POMP. When Noggin expression is decreased by siRNA, the expression of POMP is inhibited. To sum up, POMP strongly expressed in the root sheath of hair follicles, related to the development of the primary and secondary hair follicle; In addition, by adding MT/FGF5/IGF-1 or interfering with the Noggin expression to regulate the expression of POMP, to control the growth of Liaoning Cashmere goat cashmere.
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Affiliation(s)
- Jun Piao
- Faculty of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| | - Chun-Ling Xu
- Faculty of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| | - Jing-Ai Piao
- Faculty of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| | - Ming Cao
- Faculty of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
| | - Nan Huang
- Chongqing Academy of Science and Technology, Chongqing, China
| | - Mei Jin
- Faculty of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China
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Dalzell AM, Ba'Ath ME. Paediatric inflammatory bowel disease: review with a focus on practice in low- to middle-income countries. Paediatr Int Child Health 2019; 39:48-58. [PMID: 30900526 DOI: 10.1080/20469047.2019.1575056] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Inflammatory bowel disease (IBD) should be considered in any child with a persistently altered bowel habit. Growth failure may be a consequence and there may also be extra-intestinal manifestations. Oesophago-gastroduodenoscopy and colonoscopy and conventional histopathology are the diagnostic tools of choice in IBD. The identification and management of children with IBD in resource-poor settings is difficult and there are few data on its prevalence in low- and middle-income countries. The main challenges are a lack of resources and infrastructure including trained personnel in settings where there are other priorities for maintaining the health and wellbeing of children. The identification and management of children with inflammatory bowel conditions often depends on the enthusiasm, skill and commitment of a few dedicated individuals. Abbreviations: ADA: Adalimumab; CD: Crohn disease; ECCO: European Crohn's and Colitis Organisation; EEN: exclusive enteral nutrition; ESPGHAN: European Society for Paediatric Gastroenterology Hepatology and Nutrition; FMT: faecal microbiota transplantation; GDP: gross domestic product; HIC: high-income countries; IBD: inflammatory bowel disease; IBDU: inflammatory bowel disease unclassified; IC: ileocolonoscopy; IFX: infliximab; IPAA: ileal pouch anal anastomosis; LMIC: low- and middle-income countries; MH: mucosal healing; OGD: oesophago-gastroduodenoscopy; PCDAI: Paediatric Crohn's Disease Activity Index; PIBD: paediatric inflammatory bowel disease; PUCAI: Paediatric Ulcerative Colitis Activity Index; UC: ulcerative colitis; UGIT: upper gastrointestinal tract; VEO-IBD: very early-onset IBD; WLE: white light endoscopy; 5-ASA: 5 aminosalicylic acid; 6-MP: 6-mercaptopurine.
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Ishige T. Growth failure in pediatric onset inflammatory bowel disease: mechanisms, epidemiology, and management. Transl Pediatr 2019; 8:16-22. [PMID: 30881894 PMCID: PMC6382509 DOI: 10.21037/tp.2018.12.04] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 12/26/2018] [Indexed: 12/16/2022] Open
Abstract
Impairment of growth is recognized as one of the most significant complications of inflammatory bowel disease (IBD) in pediatric patients. The reported incidence of growth failure at diagnosis is 15-40% in pediatric onset Crohn's disease (CD) and 3-10% in ulcerative colitis (UC). Growth failure is associated with decreased appetite, abdominal symptoms, malabsorption due to mucosal inflammation, growth hormone (GH) resistance due to inflammation, and even genetic factors. Several population-based studies and cohort studies suggest that patients with pre-pubertal onset CD have a higher risk of growth failure at disease onset. Final adult height is still lower than that of healthy controls; however, its prevalence is generally lower than that at the disease onset. Several IBD treatments were reported to improve patients' growth. In addition to enteral nutrition therapy, treatment with anti-tumor necrosis factor (TNF) agents was reported to have favorable effects on growth of patients with pre-pubertal onset CD. Avoiding corticosteroids (CS) and achieving deep remission seems to be important to maintain optimal growth in patients with pediatric onset IBD.
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Affiliation(s)
- Takashi Ishige
- Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
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11
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Low Insulin-like Growth Factor-1 Influences Fatigue and Quality of Life in Children With Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2018; 67:616-621. [PMID: 29901552 DOI: 10.1097/mpg.0000000000002057] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE Fatigue is common among patients with inflammatory bowel disease (IBD). Proinflammatory cytokines are elevated in chronic inflammation and can induce "sickness behaviors," such as fatigue. Chronic inflammatory states also lead to growth hormone resistance, demonstrated by low levels of insulin-like growth factor (IGF-1) and elevated growth hormone. This study evaluated the relationship between IGF-1, proinflammatory cytokine levels, and fatigue in patients with IBD. METHODS In this prospective study children with IBD, ages 10 to 16 years, were recruited from a subspecialty ambulatory clinic. Participants and their parents completed age-appropriate generic and disease-specific health-related quality of life (HRQOL) instruments. Serum samples obtained at the same encounter were analyzed for Th17 cytokine and IGF-1 levels. HRQOL scores were compared to a healthy sample and HRQOL scores and cytokine levels were compared by IGF-1 z score quartiles. RESULTS A total of 67 patients with IBD were recruited, median age of 13.7 years (interquartile range, 11.7-15.3). Forty-eight (72%) had inactive disease based on Physician Global Assessment. Patients with IBD reported lower generic HRQOL (P = 0.0006) and more fatigue (P = 0.0004) than a healthy sample. Patients with IGF-1 z scores in the lowest quartile had significantly lower disease-specific HRQOL (P = 0.01) and more fatigue (P = 0.02) than the remainder of the cohort. Serum interleukin (IL)-10, IL-17A, IL-6, and interferon-γ were significantly higher in patients with IBD with IGF-1 z scores in the lowest quartile (P < 0.05). CONCLUSIONS Children with subclinical IBD experience more fatigue and lower generic HRQOL than healthy children. Lower IGF-1 z scores are associated with more fatigue, and this relationship may be mediated through proinflammatory cytokines.
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12
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Harvey S, Martinez-Moreno CG. Growth Hormone: Therapeutic Possibilities—An Overview. Int J Mol Sci 2018; 19:ijms19072015. [PMID: 29997315 PMCID: PMC6073347 DOI: 10.3390/ijms19072015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 07/06/2018] [Accepted: 07/08/2018] [Indexed: 11/16/2022] Open
Affiliation(s)
- Steve Harvey
- Department of Physiology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
| | - Carlos G Martinez-Moreno
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Campus Juriquilla, Universidad Nacional Autónoma de México, Querétaro, Qro. 76230, Mexico.
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The pre-treatment characteristics and evaluation of the effects of recombinant human growth hormone therapy in children with growth hormone deficiency and celiac disease or inflammatory bowel disease. Cent Eur J Immunol 2018; 43:69-75. [PMID: 29736148 PMCID: PMC5927175 DOI: 10.5114/ceji.2018.74875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 12/21/2017] [Indexed: 12/20/2022] Open
Abstract
The aim of the study was to investigate the coincidence of growth hormone deficiency (GHD) and celiac disease (CD) or inflammatory bowel disease (IBD) in patients referred for short stature, and to evaluate the baseline anthropometric parameters and the effectiveness of recombinant human growth hormone (rhGH) therapy in the first year in those patients (GHD+CD/IBD subgroup) in comparison to patients with GHD without CD or IBD (GHD-CD/IBD subgroup). Material and methods The study was retrospective and included 2196 short patients (height SDS [Standard Deviation Score] ≤ –1.2). 1454 patients had height SDS ≤ –2. Twenty-nine patients suffered from CD or IBD. GHD was confirmed in 419 patients with height SDS ≤ –2. The coexistence of GHD and CD or IBD was found in seven patients (GHD+CD/IBD subgroup). Results At baseline the GHD-CD/IBD subgroup did not differ significantly in chronological age, height SDS, height velocity (HV) before rhGH therapy, body weight SDS, and body mass index SDS from the GHD+CD/IBD subgroup. The improvement in height SDS within the first year of rhGH therapy was higher in the GHD+CD/IBD subgroup than in the GHD-CD/IBD subgroup and the difference was statistically significant (p<0.05). HV in the first year of rhGH therapy was also significantly higher in the GHD+CD/IBD subgroup than in the GHD-CD/IBD subgroup (p < 0.05). Conclusions In patients with chronic inflammatory disorders of the gastrointestinal tract, especially celiac disease, coexisting with GHD, rhGH therapy could be effective and should be administered together with therapy of primary gastrointestinal disease.
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Lee EJ, Moon JS, Ko JS, Yang HR, Jang JY, Kim JW, Lee KJ. Effect of the Baseline Vitamin D Level on Growth Outcome in Pediatric Crohn Disease. Pediatr Gastroenterol Hepatol Nutr 2017; 20:41-46. [PMID: 28401055 PMCID: PMC5385306 DOI: 10.5223/pghn.2017.20.1.41] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 10/13/2016] [Accepted: 10/21/2016] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Vitamin D deficiency is common in Crohn disease (CD). The aim of the study was to examine the prevalence of vitamin D deficiency and evaluate the association between vitamin D status and growth outcome in Korean pediatric CD patients. METHODS In this retrospective study, 17 children younger than 18 years old diagnosed with CD were enrolled and their serum 25-hydroxy vitamin D (25[OH]D) was checked between 2011 and 2015. We categorized the patients into two groups, Group 1 and Group 2. Group 1 included patients with serum 25(OH)D levels below 10 ng/mL, and Group 2 was for patients with a 25(OH)D serum levels between 10 ng/mL and 30 ng/mL. The z-scores for height (Htz), weight (Wtz), and body mass index (BMIz) were measured at baseline, 6 months, and 12 months. RESULTS The mean serum 25(OH)D levels of the total 65 CD patients and 17 enrolled patients were 15.64±6.9 ng/mL and 13.1±5.1 ng/mL, respectively. There was no correlation at the beginning of the study between vitamin D level and growth parameters (Htz, Wtz, BMIz) or other variables including laboratory data and Pediatric Crohn Disease Activity Index. The Htz, Wtz, and BMIz in Group 1 showed no significant improvement at 6 months and 12 months follow-up. In Group 2, Wtz and BMIz showed significant improvements sustained until 12 months of follow-up. Htz showed no significant improvement at 6 months but there was significant improvement at 12 months. CONCLUSION It seems that baseline vitamin D status affects growth outcome in pediatric CD.
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Affiliation(s)
- Eun Joo Lee
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Ju Young Jang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Ju Whi Kim
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung Jae Lee
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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Kim YJ. Nutritional concerns in pediatric inflammatory bowel disease. KOREAN JOURNAL OF PEDIATRICS 2016; 59:247-51. [PMID: 27462352 PMCID: PMC4958701 DOI: 10.3345/kjp.2016.59.6.247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 12/15/2015] [Accepted: 12/16/2015] [Indexed: 01/09/2023]
Abstract
The pathophysiology and fundamental etiologic mechanism of inflammatory bowel disease (IBD) is not well understood even though therapeutic regimens and drugs are rapidly evolutionary. IBD has complicated connections with genetic, immunologic, gut microbial, environmental, and nutritional factors. It is not clearly well known to the physicians how to feed, what nutrients are more helpful, and what food to be avoided. This review discusses the issues of growth and important nutritional concerns in the management of IBD in childhood.
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Affiliation(s)
- Yong Joo Kim
- Department of Pediatrics, Hanyang University College of Medicine, Seoul, Korea
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Gasparetto M, Guariso G. Crohn's disease and growth deficiency in children and adolescents. World J Gastroenterol 2014; 20:13219-13233. [PMID: 25309059 PMCID: PMC4188880 DOI: 10.3748/wjg.v20.i37.13219] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 04/22/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
Nutritional concerns, linear growth deficiency, and delayed puberty are currently detected in up to 85% of patients with Crohn’s disease (CD) diagnosed at childhood. To provide advice on how to assess and manage nutritional concerns in these patients, a Medline search was conducted using “pediatric inflammatory bowel disease”, “pediatric Crohn’s disease”, “linear growth”, “pubertal growth”, “bone health”, and “vitamin D” as key words. Clinical trials, systematic reviews, and meta-analyses published between 2008 and 2013 were selected to produce this narrative review. Studies referring to earlier periods were also considered if the data was relevant to our review. Although current treatment strategies for CD that include anti-tumor necrosis factor-α therapy have been shown to improve patients’ growth rate, linear growth deficiencies are still common. In pediatric CD patients, prolonged diagnostic delay, high initial activity index, and stricturing/penetrating type of behavior may cause growth deficiencies (in weight and height) and delayed puberty, with several studies reporting that these patients may not reach an optimal bone mass. Glucocorticoids and inflammation inhibit bone formation, though their impact on skeletal modeling remains unclear. Long-term control of active inflammation and an adequate intake of nutrients are both fundamental in promoting normal puberty. Recent evidence suggests that recombinant growth factor therapy is effective in improving short-term linear growth in selected patients, but is of limited benefit for ameliorating mucosal disease and reducing clinical disease activity. The authors conclude that an intense initial treatment (taking a “top-down” approach, with the early introduction of immunomodulatory treatment) may be justified to induce and maintain remission so that the growth of children with CD can catch up, ideally before puberty. Exclusive enteral nutrition has a key role in inducing remission and improving patients’ nutritional status.
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Abstract
Crohn's disease in childhood causes linear growth retardation, which has a substantial effect on management of this disease. By contrast, growth is rarely a problem in children presenting with ulcerative colitis. Depending on how growth failure is defined, approximately one-third of children with Crohn's disease have growth retardation at diagnosis. Although corticosteroids can suppress growth, decreased height at diagnosis demonstrates that this finding is a consequence of the disease and not merely an adverse effect of treatment. Both inflammation and undernutrition contribute to decreased height velocity. Increased cytokine production acts both on the hepatic expression of insulin-like growth factor 1 (IGF-1) and at chondrocytes of the growth plates of long bones. Growth hormone insensitivity caused by deranged immune function is a major mechanism in growth retardation. Resolution of inflammation is the cornerstone of treatment, but current studies on growth hormone and IGF-1 might yield therapies for those children whose inflammation is refractory to treatment.
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Affiliation(s)
- Ian R Sanderson
- Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London. 4 Newark Street, London E1 2AT, UK
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von Scheven E, Corbin KJ, Stagi S, Cimaz R. Glucocorticoid-associated osteoporosis in chronic inflammatory diseases: epidemiology, mechanisms, diagnosis, and treatment. Curr Osteoporos Rep 2014; 12:289-99. [PMID: 25001898 DOI: 10.1007/s11914-014-0228-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Children with chronic illnesses such as Juvenile Idiopathic Arthritis and Crohn's disease, particularly when taking glucocorticoids, are at significant risk for bone fragility. Furthermore, when childhood illness interferes with achieving normal peak bone mass, life-long fracture risk is increased. Osteopenia and osteoporosis, which is increasingly recognized in pediatric chronic disease, likely results from numerous disease- and treatment-related factors, including glucocorticoid exposure. Diagnosing osteoporosis in childhood is complicated by the limitations of current noninvasive techniques such as DXA, which despite its limitations remains the gold standard. The risk:benefit ratio of treatment is confounded by the potential for spontaneous restitution of bone mass deficits and reshaping of previously fractured vertebral bodies. Bisphosphonates have been used to treat secondary osteoporosis in children, but limited experience and potential long-term toxicity warrant caution in routine use. This article reviews the factors that influence loss of normal bone strength and evidence for effective treatments, in particular in patients with gastrointestinal and rheumatologic disorders who are receiving chronic glucocorticoid therapy.
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Affiliation(s)
- Emily von Scheven
- Pediatric Rheumatology, University of California, San Francisco, 505 Parnassus Avenue, Box 0105, San Francisco, CA, 94143, USA,
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Chouliaras G, Panayotou I, Margoni D, Mantzou E, Pervanidou P, Manios Y, Chrousos GP, Roma E. Circulating leptin and adiponectin and their relation to glucose metabolism in children with Crohn's disease and ulcerative colitis. Pediatr Res 2013; 74:420-6. [PMID: 23823177 DOI: 10.1038/pr.2013.114] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 03/04/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Crohn's disease (CD) and ulcerative colitis (UC) result in metabolic consequences. We assessed circulating leptin and adiponectin concentrations and examined their relations to glucose metabolism in children with CD and UC. METHODS Circulating morning fasting concentrations of leptin, adiponectin, glucose, and insulin were measured in 32 children with CD and 18 children with UC. Insulin resistance (IR) and β-cell function were evaluated by the updated homeostatic model assessments (HOMA2-IR and HOMA2-B). RESULTS Leptin was positively related to BMI z-scores overall and in the CD and the UC subgroups (P < 0.001). A negative correlation between leptin and disease activity was observed in the entire population (P = 0.034) and in the UC (P = 0.03) group. None of the assessed parameters was related to adiponectin. Fourteen percent of the participants were insulin resistant (15.6% in the CD group and 11.1% in the UC group), significantly more than expected (P < 0.001). Leptin was associated with HOMA2-IR (overall: r = 0.29, P = 0.045). Pathway analysis suggested that, overall, disease activity and BMI significantly affect leptin, which in turn is the only correlate of HOMA2-IR. CONCLUSION Disease activity was significantly and inversely related to leptin in children with inflammatory bowel disease (IBD). A significant proportion of the patients had increased IR, which is positively related to circulating leptin.
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Affiliation(s)
- Giorgos Chouliaras
- 1] First Department of Pediatrics, University of Athens, Athens, Greece [2] Research Division of Endocrinology and Metabolic Diseases, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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Dilillo D, Guazzarotti L, Galli E, Zuccotti GV. Mechanisms and management of growth impairment in children affected by inflammatory bowel disease. Expert Rev Endocrinol Metab 2013; 8:289-299. [PMID: 30780818 DOI: 10.1586/eem.13.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Growth failure is a typical complication of pediatric inflammatory bowel disease. Factors responsible for stunting are multiple, and proinflammatory cytokines such as TNF-α and IL-6 play a pivotal role. Other determinants are disease severity and location, malnutrition, increased nutritional needs, genetics and drugs. The achievement of optimal linear growth and the remission of gastrointestinal symptoms are the principal targets of pediatric inflammatory bowel disease treatment. Thus, it is very important to assess and monitor linear growth at diagnosis and during follow-up of disease until final adult height achievement. The main strategies for management or prevention of growth impairment in these children are aimed to ensure optimal nutrition, obtain a rapid and complete remission of the disease avoiding or minimizing steroid usage and consider surgical resection, in particular in case of localized ileo or ileocecal disease, to achieve remission in early or mid-puberty. In the last few years, some authors have evaluated the effects of recombinant human growth hormone treatment in children and adolescents with inflammatory bowel disease. However, further studies are needed to better assess its efficacy.
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Affiliation(s)
- Dario Dilillo
- b Department of Pediatrics, University of Milan, Luigi Sacco Hospital, Milan, Italy.
| | - Laura Guazzarotti
- a Department of Pediatrics, University of Milan, Luigi Sacco Hospital, Milan, Italy
| | - Erica Galli
- a Department of Pediatrics, University of Milan, Luigi Sacco Hospital, Milan, Italy
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Abstract
PURPOSE OF REVIEW To summarize the recent evidence that insulin-like growth factor 1 (IGF1) mediates growth effects of multiple trophic factors and discuss clinical relevance. RECENT FINDINGS Recent reviews and original reports indicate benefits of growth hormone (GH) and long-acting glucagon-like peptide 2 (GLP2) analogs in short bowel syndrome and Crohn's disease. This review highlights the evidence that biomarkers of sustained small intestinal growth or mucosal healing and evaluation of intestinal epithelial stem cell biomarkers may improve clinical measures of intestinal growth or response to trophic hormones. Compelling evidence that IGF1 mediates growth effects of GH and GLP2 on intestine or linear growth in preclinical models of resection or Crohn's disease is presented, along with a concept that these hormones or IGF1 may enhance sustained growth if given early after bowel resection. Evidence that suppressor of cytokine signaling protein induction by GH or GLP2 in normal or inflamed intestine may limit IGF1-induced growth, but protect against risk of dysplasia or fibrosis, is reviewed. Whether IGF1 receptor mediates IGF1 action and potential roles of insulin receptors are addressed. SUMMARY IGF1 has a central role in mediating trophic hormone action in small intestine. Better understanding of benefits and risks of IGF1, receptors that mediate IGF1 action, and factors that limit undesirable growth are needed.
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