Pediatric Review
Growth retardation in pediatric Crohn's disease: Pathogenesis and interventions
Raanan Shamir MD,
Moshe Phillip MD,
Arie Levine MD,
Raanan Shamir MD
Pediatric Gastroenterology Division of the Meyer Children's Hospital, Haifa
Ruth and Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Tel-Aviv
Search for more papers by this authorMoshe Phillip MD
Institute for Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, Tel Aviv
Sackler School of Medicine, Tel-Aviv University, Israel
Search for more papers by this authorCorresponding Author
Arie Levine MD
Pediatric Gastroenterology Division of the Wolfson Medical Centers, Tel Aviv
Sackler School of Medicine, Tel-Aviv University, Israel
Pediatric Gastroenterology Unit, E. Wolfson Medical Center, Sackler School of Medicine, POB 5 Holon, Israel 58100Search for more papers by this authorRaanan Shamir MD,
Moshe Phillip MD,
Arie Levine MD,
Raanan Shamir MD
Pediatric Gastroenterology Division of the Meyer Children's Hospital, Haifa
Ruth and Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Tel-Aviv
Search for more papers by this authorMoshe Phillip MD
Institute for Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, Tel Aviv
Sackler School of Medicine, Tel-Aviv University, Israel
Search for more papers by this authorCorresponding Author
Arie Levine MD
Pediatric Gastroenterology Division of the Wolfson Medical Centers, Tel Aviv
Sackler School of Medicine, Tel-Aviv University, Israel
Pediatric Gastroenterology Unit, E. Wolfson Medical Center, Sackler School of Medicine, POB 5 Holon, Israel 58100Search for more papers by this authorAbstract
Growth retardation (GR) may pose a significant challenge to the quality of life and the proper management of children and adolescents with Crohn's disease (CD). It can occur in a significant proportion of patients, and may precede clinical evidence of bowel disease. Current evidence suggests that GR is a complex interaction between nutritional status, inflammation, disease severity, and genotype, which causes resistance to the effects of growth hormone. Recent research has identified a key role for the inflammatory cytokines TNF alpha, IL-6, and IL1 beta. This review summarizes current knowledge as well as gaps in our understanding of the mechanisms involved and the usefulness of the different treatment modalities in promoting growth in CD patients.
(Inflamm Bowel Dis 2007)
REFERENCES
- 1 Newby E, Sawczenko A, Thomas A, et al. Interventions for growth failure in childhood Crohn's disease. Cochrane Database Syst Rev. 2005; 3: CD003873.
- 2 Cezard JP, Touati G, Alberti C, et al. Growth in pediatric Crohn's disease. Horm Res. 2002; 58(Suppl 1): 11–15.
- 3 Kleinman RE, Baldassano RN, Caplan A, et al. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Nutrition support for pediatric patients with inflammatory bowel disease: a clinical report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2004; 39: 15–27.
- 4 Puntis J, McNeish AS, Allan RN. Long term prognosis of Crohn's disease with onset in childhood and adolescence. Gut. 1984; 25: 329–336.
- 5 Markowitz J, Grancher K, Rosa J, et al. Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1993; 16: 373–380.
- 6 Ferguson A, Sedgwick DM. Juvenile onset inflammatory bowel disease: height and body mass index in adult life. BMJ. 1994; 308: 1259–1263.
- 7 Hildebrand H, Karlberg J, Kristiansson B. Longitudinal growth in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1994; 18: 165–173.
- 8 Sawczenko A, Ballinger AB, Savage MO, et al. Clinical features affecting final adult height in patients with pediatric-onset Crohn's disease. Pediatrics. 2006; 118: 124–129.
- 9 Seidman EG. Nutritional management of inflammatory bowel disease. Gastroenterol Clin North Am. 1989; 18: 129–155.
- 10 Belli DC, Seidman E, Bouthillier L, et al. Chronic intermittent elemental diet improves growth failure in children with Crohn's disease. Gastroenterology. 1988; 94: 603–610.
- 11 Phillip M, Moran O, Lazar L. Growth without growth hormone. J Pediatr Endocrinol Metab. 2002; 15: 1267–1272.
- 12 Cheng RY, Bireli LA, Lum NL, et al. Expression of hepatic genes, especially IGF-binding protein-1, correlating with serum corticosterone in microarray analysis. J Mol Endocrinol. 2004; 32: 257–278.
- 13 Shamir R, Wilschanski M. Malnutrition. In: S Altschuler, C Liacouras, editors. Textbook of clinical pediatric gastroenterology. Philadelphia: Churchill Livingstone. 1998: 81–88.
- 14 Sitrin MD. Nutrition support in inflammatory bowel disease. NCP Bull. 1992; 7: 53–60.
- 15 Al-Jaouni R, Schneider SM, Piche T, et al. Effect of steroids on energy expenditure and substrate oxidation in women with Crohn's disease. Am J Gastroenterol. 2002; 97: 2843–2849.
- 16 Gavin J, Anderson CE, Bremner AR, et al. Energy intakes of children with Crohn's disease treated with enteral nutrition as primary therapy. J Hum Nutr Diet. 2005; 18: 337–342.
- 17 Azcue M, Rashid M, Griffiths A, et al. Energy expenditure and body composition in children with Crohn's disease: effect of enteral nutrition and treatment with prednisolone. Gut. 1997; 41: 203–208.
- 18 Cormier K, Mager D, Bannister L, et al. Resting energy expenditure in the parenterally fed pediatric population with Crohn's disease. J Parenter Enteral Nutr. 2005; 29: 102–107.
- 19 Seidman E, LeLeiko N, Ament M, et al. Nutritional issues in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1991; 12: 424–438.
- 20 Burnham JM, Shults J, Semeao E, et al. Body-composition alterations consistent with cachexia in children and young adults with Crohn disease. Am J Clin Nutr. 2005; 82: 413–420.
- 21 Sermet-Gaudelus I, Souberbielle JC, Azhar I, et al. Insulin-like growth factor 1 correlates with lean body mass in cystic fibrosis patients. Arch Dis Child. 2003; 88: 956–961.
- 22 Smith WJ, Underwood LE, Clemmons DR. Effects of caloric or protein restriction on insulin-like growth factor-I (IGF-I) and IGF-binding proteins in children and adults. J Clin Endocrinol Metab. 1995; 80: 443–449.
- 23 Kaaks R, Lukanova A. Energy balance and cancer: the role of insulin and insulin like growth factor 1. Proc Nutr Soc. 2001; 60: 91–106.
- 24 Maor G, Rochwerger M, Sagiv Y, et al. Leptin acts as a growth factor on the chondrocytes of skeletal growth centers. J Bone Mineral Res. 2002; 17: 1034–1043.
- 25 Gat-yablonski G, Ben-Ari T, Shtaif B, et al. Leptin reverses the inhibitory effect of caloric restriction on longitudinal growth. Endocrinology. 2004; 145: 343–350.
- 26 Saha MT, Ruuska T, Laippala P, et al. Growth of prepubertal children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1998; 26: 310–314.
- 27 Griffiths AM, Nguyen P, Smith C, et al. Growth and clinical course of children with Crohn's disease. Gut. 1993; 34: 939–943.
- 28 Wine E, Reif S, Leshinsky-Silver E, et al. Pediatric Crohn's disease and growth retardation: the role of genotype, phenotype and disease severity. Pediatrics. 2004; 114: 1281–1286.
- 29 Motil KJ, Grand RJ, Maletskos CJ, et al. The effect of disease, drug, and diet on whole body protein metabolism in adolescents with Crohn disease and growth failure. J Pediatr. 1982; 101: 345–351.
- 30 Motil KJ, Grand RJ, Davis-Kraft L, et al. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology. 1993; 105: 681–691.
- 31 Blodgeff FM, Burgin L, Iezzoni D, et al. Effects of prolonged cortisone therapy on the statural growth, skeletal maturation and metabolic status of children. N Engl J Med. 1956; 254: 636–641.
- 32 Levine A, Broide E, Stein M, et al. Evaluation of oral budesonide for treatment of mild and moderate exacerbations of Crohn's disease in children. J Pediatr. 2002; 140: 75–80.
- 33 Gronbek H, Thogersen T, Frystyk J, et al. Low free and total insulin-like growth factor I (IGF-I) and IGF binding protein-3 levels in chronic inflammatory bowel disease: partial normalization during prednisolone treatment. Am J Gastroenterol. 2002; 97: 673–678.
- 34 Akobeng AI, Clayton PE, Miller V, et al. Low serum concentrations of insulin-like growth factor-I in children with active Crohn disease. Effect of enteral nutritional support and glutamine supplementation. Scand J Gastroenterol. 2002; 37: 1422–1427.
- 35 Thomas AG, Holly JM, Taylor F, et al. Insulin like growth factor-1, insulin like growth factor binding protein-1, and insulin in childhood Crohn's disease. Gut. 1993; 34: 944–947.
- 36 Corkins MR, Gohil AD, Fitzgerald JF. The insulin like growth factor axis in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2003; 36: 228–234.
- 37 DiFedele LM, He J, Bonkowski EL, et al. Tumor necrosis factor alpha blockade restores growth hormone signaling in murine colitis. Gastroenterology. 2005; 128: 1278–1291.
- 38 De Benedetti F, Alonzi T, Moretta A, et al. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-1. A model for stunted growth in children with chronic inflammation. J Clin Invest. 1997; 99: 643–650.
- 39 Denson LA, Held MA, Menon RK, et al. Interleukin-6 inhibits hepatic growth hormone signaling via up-regulation of Cis and Socs-3. Am J Physiol. 2003; 284: G646–G654.
- 40 Ballinger AB, Azooz O, El Haj T, et al. Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis. Gut. 2000; 46: 694–700.
- 41 Siegel SA, Shealy DJ, Nakada MT, et al. The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine. 1995; 7: 15–25.
- 42 Ladner KJ, Caligiuri MA, Guttridge DC. Tumor necrosis factor-regulated biphasic activation of NF-kappa B is required for cytokine-induced loss of skeletal muscle gene products. J Biol Chem. 2003; 278: 2294–2303.
- 43 Martensson K, Chrysis D, Savendahl A, et al. Interleukin-1beta and TNF-alpha act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones. J Bone Miner Res. 2004; 19; 1805–1812.
- 44 Franchimont D, Roland S, Gustot T, et al. Impact of infliximab on serum leptin levels in patients with Crohn's disease. J Clin Endocrinol Metab. 2005; 90: 3510–3516.
- 45 Vespasiani Gentilucci U, Caviglia R, Picardi A, et al. Infliximab reverses growth hormone resistance associated with inflammatory bowel disease. Aliment Pharmacol Ther. 2005; 21: 1063–1071.
- 46 Silverstrini G, Ballanti P, Patacchioli FR, et al. Evaluation of apoptosis and the glucocorticoid receptor in the cartilage growth plate and metaphyseal bone cells of rats after high dose treatment with corticosterone. Bone. 2000; 26: 33–42.
- 47 Baron J, Huang Z, Oerter KE, Bacher JD, et al. Dexamethasone acts locally to inhibit longitudinal bone growth in rabbits. Am J Physiol. 1992; 263: 489–492.
- 48 Smink JJ, Gresnigt MG, Hamers N, et al. Short term glucocorticoid treatment of prepubertal mice decreases growth and IGF1 expression in the growth plate. J Endocrinol. 2003; 177: 381–388.
- 49 Sawczenko A, Azooz O, Paraszczuk J, et al. Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C polymorphism in children. Proc Natl Acad Sci U S A. 2005; 102: 13260–13265.
- 50 Levine A, Shamir R, Wine E, et al. TNF promoter polymorphisms modulate growth retardation and disease severity in pediatric Crohn's disease. Am J Gastroenterol. 2005; 100: 1598–1604.
- 51 Russell RK, Drummond HE, Nimmo ER, et al. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth parameters in early-onset inflammatory bowel disease. Gut. 2006; 55: 1114–1123.
- 52 Bannerjee K, Camacho-Hubner C, Babinska K, et al. Anti-inflammatory and growth-stimulating effects precede nutritional restitution during enteral feeding in Crohn disease. J Pediatr Gastroenterol Nutr. 2004; 38: 270–275.
- 53 Beattie RM, Camacho-Hubner C, Wacharasindhu S, et al. Responsiveness of IGF-I and IGFBP-3 to therapeutic intervention in children and adolescents with Crohn's disease. Clin Endocrinol. 1998; 49: 483–489.
- 54 Zachos M, Tondeur M, Griffiths AM. Enteral nutritional therapy for inducing remission of Crohn's disease. Cochrane Database Syst Rev. 2001; (3): CD000542.
- 55 Thomas AG, Taylor F, Miller V. Dietary intake and nutritional treatment in childhood Crohn's disease. J Pediatr Gastroenterol Nutr. 1993; 17: 75–81.
- 56 Sanderson IR, Udeen S, Davies PS, et al. Remission induced by an elemental diet in small bowel Crohn's disease. Arch Dis Child. 1987; 62: 123–127.
- 57 Papadopoulou A, Rawashdeh MO, Brown GA, et al. Remission following an elemental diet or prednisolone in Crohn's disease. Acta Paediatr. 1995; 84: 79–83.
- 58 Heuschkel RB, Menache CC, Megerian JT, et al. Enteral nutrition and corticosteroids in the treatment of acute Crohn's disease in children. J Pediatr Gastroenterol Nutr. 2000; 31: 8–15.
- 59 Ludvigsson JF, Krantz M, Bodin L, et al. Elemental versus polymeric enteral nutrition in paediatric Crohn's disease: a multicenter randomized controlled trial. Acta Paediatr. 2004; 93: 327–335.
- 60 Wilschanski M, Sherman P, Pencharz P, et al. Supplementary enteral nutrition maintains remission in paediatric Crohn's disease. Gut. 1996; 38: 453–458.
- 61 Aiges H, Markowitz J, Rosa J, et al. Home nocturnal supplemental nasogastric feedings in growth-retarded adolescents with Crohn's disease. Gastroenterology. 1989; 97: 905–910.
- 62 Cosgrove M, Jenkins HR. Experience of percutaneous endoscopic gastrostomy in children with Crohn's disease. Arch Dis Child. 1997; 76: 141–143.
- 63 Pashankar D, Israel DM. Gastrostomy in children with Crohn's disease. Arch Dis Child. 1997; 77: 369.
- 64 Johnson T, Macdonald S, Hill SM, et al. Treatment of active Crohn's disease in children using partial enteral nutrition with liquid formula: a randomized controlled trial. Gut. 2006; 55: 356–361.
- 65 Afzal NA, Davies S, Paintin M, et al. Colonic Crohn's disease in children does not respond well to treatment with enteral nutrition if the ileum is not involved. Dig Dis Sci. 2005; 50: 1471–1475.
- 66 Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology. 2000; 119: 895–902.
- 67 Borrelli O, Bascietto C, Viola F, et al. Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn's disease. Dig Liv Dis. 2004; 36: 342–347.
- 68
Walters TD,
Gilman AR,
Griffiths AM.
Infliximab therapy restores normal growth in children with chronically active severe Crohn's disease refractory to immunomodulatory therapy.
J Pediatr Gastroenterol Nutr.
2005;
40:
646A.
10.1002/j.1536-4801.2005.tb01091.x Google Scholar
- 69 Griffiths AM, Hyams J, Crandall W, et al. Height of growth delayed children and active Crohn's disease improves during tratment with infliximab. Gastroenterology. 2006; 130(Suppl 2): A12.
- 70 Slonim AE, Bulone L, Damore MB, et al. A preliminary study of growth hormone therapy for Crohn's disease. N Engl J Med. 2000; 342: 1633–1637.
- 71 Mauras N, George D, Evans J, et al. Growth hormone has anabolic effects in glucocorticosteroid-dependent children with inflammatory bowel disease: a pilot study. Metabolism. 2002; 51: 127–135.
- 72 Calenda KA, Schornagel IL, Sadeghi-nejad A, et al. Effect of Recombinant growth hormone treatment on children with Crohn's disease and short stature: a pilot study. Inflamm Bowel Dis. 2005; 11: 435–441.
- 73 Kirschner BS, Sutton MM. Somatomedin-C levels in growth-impaired children and adolescents with chronic inflammatory bowel disease. Gastroenterology. 1986; 91: 830–836.
- 74 Walker-Smith JA. Management of growth failure in Crohn's disease. Arch Dis Child. 1996; 75: 351–354.
- 75 Alperstein G, Daum F, Fisher SE, et al. Linear growth following surgery in children and adolescents with Crohn's disease: relationship to pubertal status. J Pediatr Surg. 1985; 20: 129–133.
- 76 Lipson AB, Savage MO, Davies PS, et al. Acceleration of linear growth following intestinal resection for Crohn disease. Eur J Pediatr. 1990; 149: 687–690.
- 77 McLain BI, Davidson PM, Stokes KB, et al. Growth after gut resection for Crohn's disease. Arch Dis Child. 1990; 65: 760–762.
- 78 Griffiths AM, Wesson DE, Shandling B, et al. Factors influencing postoperative recurrence of Crohn's disease in childhood. Gut. 1991; 32: 491–495.
- 79 Dokucu AI, Sarnacki S, Michel JL, et al. Indications and results of surgery in patients with Crohn's disease with onset under ten years of age: a series of 18 patients. Eur J Pediatr Surg. 2002; 12: 180–185.
- 80 Hommes D, Baert F, van Assche G, et al. A Randomized controlled trial evaluating the ideal medical management for Crohn's disease (CD): top down versus step-up strategies. Gastroenterology. 2005; 128: 292A.
