TY - JOUR
AU - Grand, Richard J.
AB - Ulcerative colitis and Crohn's disease in children and adolescents have unique aspects that differentiate them from inflammatory bowel disease (IBD) in adults. Among these features are: Physical and emotional growth of children and adolescents resulting in a changing baseline for evaluation of treatment efficacy, and a vulnerable environment for diseases that affect nutritional and immune status. Furthermore, growth failure due to IBD or resulting from pharmacologic treatment of IBD, or both, is an important and unique aspect of pediatric IBD; The fundamental implication of long-standing disease in patients diagnosed in childhood with potential increased risk of long-term complications, including cancer, surgery, quality-of-life issues, hepatobiliary disease, and adverse drug events; The pervasive lack of evidence-based studies involving children and adolescents with IBD. Phase III drug trials rarely involve children and young adolescents, and therefore information regarding optimal dosing and side effects of standard medications is lacking; and The opportunity to determine the etiopathogenesis of IBD and to intervene in a population with earlyonset disease in which the duration of disease is more reliably determined. These opportunities give impetus to the development of a national or international pediatric IBD database to serve as a resource for important epidemiologic, demographic, genetic, and outcome studies. With the specific purpose of addressing these and other unique aspects of pediatric IBD and to promote an interactive exchange of ideas among professionals involved in the care of children and adolescents with IBD, a conference entitled Controversies in Pediatric Inflammatory Bowel Disease was held in Cincinnati, Ohio, on June 14-15, 1997. The conference was sponsored by Children's Hospital Medical Center, the University of Cincinnati, and the Crohn's & Colitis Foundation of America. Support for the conference was provided by Procter & Gamble Pharmaceuticals and Solvay Pharmaceuticals. The invited faculty were directed to encourage evidence-based discussion relating to these issues. The conference was divided into six sessions: Etiopathogenesis of Inflammatory Bowel Disease: A Pediatric Perspective Initial Maintenance Therapy (Relapse Prevention) and Therapy of Steroid Resistance and Dependence Perianal Disease, Growth Failure, and Quality of Life Malignancy and Aneuploidy: Prevention and Early Detection Hepatobiliary Complications of Inflammatory Bowel Disease: Overview of the Issues Management of Severe Colitis/Ileocolitis In addition to providing a state-of-the-art review, we hope that these summaries will focus the clinical and basic research challenges relating to pediatric IBD. Session 1. Etiopathogenesis of Inflammatory Bowel Disease: A Pediatric Perspective Ernest Seidman Hôpital Sainte-Justine, Montreal, Quebec, Canada Introduction Both Crohn's disease and ulcerative colitis occur frequently in the pediatric age group, with a peak incidence in the second decade of life. Approximately 25% of patients with these diseases are children (1). These two disorders, commonly grouped together as chronic idiopathic inflammatory bowel disease (IBD), share many similarities in their epidemiologic, immunologic, clinical, and therapeutic characteristics (2). Despite intensive research efforts, their etiology remains unknown. The available evidence suggests that IBD results from a genetically conditioned susceptibility to immune-mediated bowel injury, which is triggered by one or more environmental factors (Fig. 1). A major emphasis of recent IBD research is aimed at understanding the imbalance in the regulatory cytokines that normally control and limit intestinal inflammation (3). However, few such studies have been carried out in pediatric patients (4). Fig. 1. Open in new tabDownload slide Hypothetical stages in the multifactorial pathogenesis of IBD. This session reviewed various aspects of the etiopathogenesis of IBD from the pediatric perspective. Ernie Seidman, M.D., Hôpital Sainte-Justine and the University of Montreal, Quebec, Canada, organized and moderated this session. Discussants were Philip Sherman M.D., from the Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada; Stephan Targan, M.D., from the IBD Center at Cedars-Sinai Medical Center and UCLA, Los Angeles, California; R. Balfour Sartor, M.D., from the University of North Carolina School of Medicine, Chapel Hill, North Carolina; Andrew Wakefield, F.R.C.S., from the Royal Free Hospital School of Medicine in London, England; Claudio Fiocchi, M.D., from Case Western Reserve School of Medicine, Cleveland, Ohio; and Barry Wershil, M.D., of Children's Hospital and Harvard Medical School, Boston, Massachusetts. The following is a brief summary of their presentations and conclusions. Genetic The importance of genetic susceptibility in the pathogenesis of IBD was summarized by Dr. Philip Sherman. Several studies documented the increased prevalence of IBD among family members (5–9). Indeed, a family history in a first-degree relative is the most important risk factor for the development of IBD. In contrast, IBD has very rarely been described in spouses. Notable is the high rate of disease concordance for Crohn's disease among monozygotic compared with dizygotic twins (10). Although all pairs of monozygotic twins have been concordant for the type of IBD, not all twins will be affected. Thus although Crohn's disease and ulcerative colitis have distinct genetic bases, no combination of genes is alone sufficient for the development of either disease. Genetic factors appear to be particularly important for pediatric IBD, with a family history 2.3 times more common than in adults (11). The identification of genes that may predispose to the development of IBD was the subject of recent studies. Two approaches have been used: identification of individual candidate genes and linkage-analysis studies. Associations with major histocompatibility complex (MHC) class II antigens (11), adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1; 13), tumor necrosis factor-α (TNF-α; 14), and the interleukin-1 (IL-1)-receptor antagonist (15) have been reported. However, the candidate gene approach has failed to identify IBD susceptibility genes for the majority of patients. Linkage-analysis studies in sibling pairs with IBD have been more successfully applied to the search for susceptibility genes. Hugot et al. (16) identified a possible Crohn's disease locus on chromosome 16, designated IBD 1, which confirmed a 1.3-fold relative risk to siblings in a study from France. This linkage was also shown in cases of Crohn's disease in a study from the United States by Ohmen et al. (17). Another group in England (18) found evidence of susceptibility loci for both Crohn's disease and ulcerative colitis on chromosomes 3, 7, and 12. The highest lod score (5.47) was obtained with the marker D12S83 on chromosome 12. Examining ulcerative colitis sib-pairs alone, additional linkage was suggested on chromosomes 2 and 6. The latter observation is in keeping with the earlier report of this group on the association of ulcerative colitis and DRB1 and DBQ1 genes of the HLA locus on chromosome 6 (19). A concentrated international effort to amass a sufficient pediatric cohort of familial IBD will be necessary to successfully unravel the susceptibility genes for IBD in young patients. Genetic Associations and Subclinical Markers in IBD Subgroups Dr. Stephan Targan expanded on the relation between genes and IBD. He presented evidence suggesting that distinct types of mucosal inflammation may be the primary feature of different types of IBD with similar phenotypes and that clinical manifestations result from different combinations of genetic and subclinical markers. Among patients with ulcerative colitis, inconsistent genetic associations with different human leukocyte antigen (HLA) haplotypes (DR2, DR3DQ2, or DR5) in various populations are thought to be indicative of the heterogeneity between the ethnic groups' genetic pools (20–22). Dr. Targan also suggested that the presence of antineutrophil cytoplasmic antibodies with a perinuclear staining pattern (pANCA) may serve as a useful subclinical marker, allowing stratification of patients with ulcerative colitis (23). The majority of pediatric patients with ulcerative colitis are also pANCA positive (23), as has its reactivity with a specific autoantigen, histone H1 (26). Family studies showed that pANCA is also present in some clinically healthy relatives of patients with ulcerative colitis (29). Several lines of evidence also suggest that pANCA may serve as a subclinical marker of certain types of patients, such as those who develop pouchitis (33). Anti-Saccharomyces cervisiae antibodies (ASCA) have been found in the serum of the majority of patients with Crohn's disease, including those studied in the pediatric age group (35). The minority (10-15%) of patients with Crohn's disease who are pANCA positive generally have an “ulcerative colitis”-like phenotype (36). It is anticipated that by combining data on clinical presentation and subclinical markers with defined genetic abnormalities, clinicians will be better able to predict the disease course and to identify specifically targeted therapeutic modalities for IBD. Role of Resident Microbial Flora Dr. Balfour Sartor reviewed the substantial clinical and experimental evidence that suggests that the chronic intestinal inflammation in IBD is due to an abnormally heightened immune response to the normal, resident luminal bacterial components in genetically susceptible hosts (37). The lumen of the distal small bowel and colon contains high concentrations of predominantly anaerobic bacteria, bacterial cell-wall polymers, peptidoglycanpolysaccharide (PG-PS), and toxins, lipopolysaccharide (LPS), as well as chemotactic peptides, N-formylmethionyl-leucyl-phenylalanine (fMLP), each capable of activating mucosal immune cells. The latter then secrete proinflammatory cytokines, which are potent inducers of local inflammation (38). Uptake of these bacterial components is further enhanced as a result of the inflammation, potentially magnifying the aberrant local inflammatory response, causing enterocyte dysfunction, as well as resulting in extraintestinal manifestations of IBD. The most compelling evidence that normal resident bacteria are involved in the intestinal and systemic inflammatory response in IBD is the consistent demonstration that chronic gastrointestinal and joint inflammation are absent when experimental models of IBD are induced in germ-free animals (39). These include indomethacinand carrageenan-induced colitis, HLA B27 transgenic, as well as IL-2 and IL-10 knockout mice. Experimental studies also support the concept that host genetic susceptibility is critical to determining the severity and chronicity of intestinal and extraintestinal inflammation in response to components of the bacterial flora (39–41). Determining which luminal bacteria have a dominant role in stimulating inflammation, as opposed to mucosal protection, may offer new therapeutic insights into IBD. Furthermore, elucidating the mechanisms of genetic susceptibility, such as inadequate downregulation of inflammation, may make it possible to alter the natural history of IBD. Role of Infections Early in Life: The Measles Controversy Dr. Andrew Wakefield stressed the importance of an initial priming event as well as a later triggering factor for IBD to develop in a genetically predisposed individual (Fig. 1). He contended that in Crohn's disease, the priming event occurs early in life, perhaps during infancy. Among risk factors for IBD are perinatal infectious exposures (42). Diarrheal disease is significantly more common in infants who later develop Crohn's disease (43–45). Among infectious agents encountered early in life, Dr. Wakefield argued that exposure to the measles virus may result in Crohn's disease later (46). The epidemiologic evidence that Crohn's disease is frequent in individuals exposed to measles virus in utero is particularly striking (47). Furthermore, Dr. Wakefield's group confirmed the persistence of measles virus particles in intestinal tissue in Crohn's disease (48,49). However, persistent measles infection is thought to be insufficient, of itself, to produce Crohn's disease. An additional triggering event is believed to be necessary (Fig. 1). Among these, Dr. Wakefield proposed that reexposure to measles virus, either naturally or via revaccination, might provide a specific and potent trigger for expression of the disease. The measles hypothesis was strengthened by evidence from a cohort study suggesting an increased risk of IBD in individuals given live attenuated measles vaccine in early childhood (50). More recently, however, another case-control study (51) found no difference in measles vaccination rates (56 vs. 57%) for patients with IBD (n = 140) compared with matched controls (n = 280). No evidence was found supporting the hypothesis that measles vaccination in childhood predisposes to the later development of IBD [odds ratio (OR), 0.97], Crohn's disease (OR, 1.08), or ulcerative colitis (OR, 0.84). Nevertheless, as pointed out by Dr. Wakefield, other hypotheses, including autoimmunity, primary immune defects, and an aberrant immune response to enteric flora, failed to provide an explanation for the emergence and sustained increase in the incidence of Crohn's disease in the latter half of this century. Autoimmunity The classic definition of autoimmune disorders encompasses conditions for which the clinical manifestations are the direct consequence of the immune system's inappropriately recognizing as “non-self” normal self antigens. Another possibility is the mounting of a response against antigens normally “hidden” from the immune system. In either case, an antibody-dependent or cell-mediated immune response ensues, leading to tissuespecific destruction and subsequent inflammation (52). Evidence from studies in adults was presented by Dr. Fiocchi, and supports the presence of both circulating and mucosal autoantibodies in Crohn's disease and ulcerative colitis (53). The evidence is stronger for ulcerative colitis, in agreement with its possible Th2 cytokine response, in contrast with the Th2 pattern seen in Crohn's disease. However, the distinction between the protective effect of a Th2 response and the damaging nature of a Th1 response has become blurred by recent data showing that both are potentially pathogenic (54). A novel approach to autoimmunity proposed by Dr. Fiocchi relates to the relative resistance of mucosal T cells to apoptosis in Crohn's disease (55). He suggested that immune-mediated injury to the gut could result from the local accumulation of activated cells that are recruited in large numbers, coupled to their resistance to apoptosis and inappropriate survival. The resident immune cells, constantly stimulated by luminal antigens, both bacterial and dietary, could be sufficient to induce their overactivation, and subsequently, to a loss of local tolerance. The resulting intercellular interactions may lead to autoimmunity and immune-mediated damage to the closely approximated mucosal microenvironment, the intestinal epithelial cells. Intestinal Permeability One of the long-standing controversies in the pathogenesis of IBD, the role of altered intestinal permeability, was discussed by Dr. B. Wershil. Among the important functions of the gastrointestinal tract are to digest and absorb nutrients while effectively excluding luminal antigens. Inflammation leads to a breakdown in intestinal barrier function, resulting in an increase in intestinal permeability to luminal macromolecular antigens and toxins (56). However, the relation between altered intestinal permeability and IBD has remained controversial. Part of the dilemma lies in the inaccuracies of predicting true intestinal permeability by measuring the rate and magnitude of the recovery of probe molecules in the urine (57). Numerous studies documented an increased intestinal permeability in Crohn's disease, suggesting that defective barrier function may be an etiologic factor (58). This hypothesis was tested by examining intestinal permeability in asymptomatic relatives of patients with IBD (59–65). The results of these studies have been inconsistent in their conclusions. The contradictory results are due in part to the lack of ideal probes, the relatively limited numbers of subjects examined, methodologic differences that render comparison between studies difficult, and the lack of proof of elimination of confounding factors (alcohol, etc.), or subclinical disease. It is likely that a secondary increase in permeability plays a role in determining the clinical course of IBD (Fig. 1). However, there is no strong evidence supporting the hypothesis that abnormal intestinal permeability is a primary etiologic factor in IBD. Indeed, were it the case, IBD would be more common among malnourished, chronically infected children in the developing world, where it is in fact rare. References 1.Grand RJ, Ramakrishna J, Calenda KA. Inflammatory bowel disease in the pediatric patient. Gastroenterol Clin North Am 1995; 24:613-32. 2.Inflammatory bowel diseases. In: Roy CC, Silverman A, Alagille D, eds. Pediatric clinical gastroenterology. 4th ed. St. Louis: Mosby Year Book, 1995:427-93. 3.MacDermott RP. Alterations in the mucosal immune system in ulcerative colitis and Crohn's disease. Med Clin North Am 1994; 78:1207-31. 4.Dionne S, D'Agata ID, Hiscott J, Duhaime A, Seidman EG. Quantitative PCR analysis of TNF-α and IL-1b mRNA levels in pediatric IBD mucosal biopsies. Dig Dis Sci 1997;42:1557-66. 5.Yang H, McElree C, Roth C-P, Shanahan F, Targan SR, Rotter JI. Familial empirical risk for inflammatory bowel disease: differences between Jews and non-Jews. Gut 1993;34:517-24. 6.Peeters M, Nevens H, Baert F, Hiele M, De Meyer AM, Vlietinck R. Familial aggregation in Crohn's disease: increased age-adjusted risk and concordance in clinical characteristics. Gastroenterology 1996;111:597-603. 7.Bayless TM, Tokayer AZ, Polito II JM, Quaskey SA, Mellits D, Harris ML. Crohn's disease: concordance for site and clinical type in affected family members potential hereditary influences. Gastroenterology 1996;111:573-9. 8.Lee JCW, Lennard-Jones JE. Inflammatory bowel disease in 67 families each with three or more affected first-degree relatives. Gastroenterology 1996;111:587-96. 9.Cottone M, Brignola C, Rosselli M, et al. Relationship between site of disease and familiar occurrence in Crohn's disease. Dig Dis Sci 1997;42:129-32. 10.Tysk C, Lindberg E, Jamerot G, Floderus-Myrhed B. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins: a study of heritability and the influence of smoking. Gut 1988;29:990-6. 11.Polito JM II, Childs B, Mellits ED, Tokayer AZ, Harris ML, Bayless TM. Crohn's disease: influence of age at diagnosis on site and clinical type of disease. Gastroenterology 1996;111:580-6. 12.Yang H, Rotter JI, Toyoda H, et al. Ulcerative colitis: a genetically heterogeneous disorder defined by genetic (HLA Class II) and subclinical (antineutrophil cytoplasmic antibodies) markers. J Clin Invest 1993;92:1080-4. 13.Yang H, Vora DK, Targan SR, Toyoda H. Beaudet AL, Rotter J. Intercellular adhesion molecule 1 gene associations with immunologic subsets of inflammatory bowel disease. Gastroenterology 1995;109:440-8. 14.Plevy SE, Targan SR, Yang HY, Fernandez D, Rotter JI, Toyoda H. Tumor necrosis factor microsatellites define a Crohn's diseaseassociated haplotype on chromosome 6. Gastroenterology 1996; 110:1053-60. 15.Mansfield JC, Holden H, Tarlow JK, et al. Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist. Gastroenterology 1994; 106: 637-42. 16.Hugot JP, Laurent-Puig P, Gower-Rousseau C, et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature 1996;379:821-3. 17.Ohmen JD, Yang H-Y, Yamamoto KK, et al. Susceptibility locus for inflammatory bowel disease on chromosome 16 has a role in Crohn's disease, but not ulcerative colitis. Hum Mol Genet 1996; 5:1679-83. 18.Satsangi J, Parkes M, Louis E, et al. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nature Genet 1996; 14:199-202. 19.Satsangi J, Welsh KI, Bunce M, et al. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet 1996;347: 1212-7. 20.Yang H, Rotter JI. The genetics of inflammatory bowel disease. In: Targan SR, Shanahan F, eds. Inflammatory bowel disease: from bench to bedside. Baltimore: Williams & Wilkins 1994:32-64. 21.Toyoda H, Wang S-J, Yang H, et al. Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology 1993;104:741-8. 22.Duerr RH, Chensny LJ, Wong CT, Neigut DA. Homozygosity of an HLA class II group haplotype is associated with pANCApositive and familial ulcerative colitis. Gastroenterology 1995; 108:A812. 23.Targan SR, Landers CJH, MacDermott RP, Vidrich A. Perinuclear antineutrophil cytoplasmic antibodies are spontaneously produced by B-cells from involved and uninvolved mucosa of ulcerative colitis patients. J Immunol 1995;155:3262-7. 24.Winter HS, Landers CJ, Winkelstien A, Vidrich A, Targan SR. Antineutrophil cytoplasmic antibodies in children with ulcerative colitis. J Pediatr 1994;125:707-11. 25.Seidman EG, Ruemmele R, Landers C, Gaiennie J, Braun J, Targan SR. Disease specific diagnostic accuracy of new serological tests in pediatric IBD. Gastroenterology 1997;112(4):A1087. 26.Eggena MP, Targan SR, Vidrich A, et al. Histone H1: the UCspecific PANCA target antigen. FASEB J 1996;10:463. 27.Shanahan F, Duerr R, Landers C, et al. Neutrophil autoantibodies in ulcerative colitis: a family study with evidence for genetic heterogeneity. Gastroenterology 1992;103:456-61. 28.Eggena M, Targan SR, Iwanczyk L, Vidrich A, Gordon LK, Braun J. Phage display cloning and characterization of an immunogenic marker (perinuclear anti-neutrophil cytoplasmic antibody) in ulcerative colitis. J Immunol 1996;156:4005-11. 29.Satsangi J, Landers C, Welsh K, Koss K, Targan S, Jewell DP. ANCA and HLA genes in North European patients with ulcerative colitis. Gastroenterology 1996;110:A1009. 30.Vecchi M, Gionchetti P, Bianchi MB, et al. pANCA and development of pouchitis in ulcerative colitis patients after protocolectomy and ileoanal pouch anastomosis. Lancet 1994;334:886-7. 31.Sandborn WJ, Landers CJ, Tremaine SJ, Targan SR. Antineutrophil cytoplasmic antibody correlates with chronic pouchitis after ileal pouch-anal-anastomosis. Am J Gastroenterol 1995;90: 740-7. 32.Fleshner PR, Plevy SE, Landers CJ, Targan SR. A rise in PANCA titre after ileal pouch anal anastomosis for ulcerative colitis may predict early pouchitis. Gastroenterology 1996; 110:A907. 33.Sandborn WJ, Landers CJ, Steiner BL, Tremaine WJ, Targan SR. Association of antineutrophil cytoplasmic antibody (ANCA) is unexpectedly high in patients with treatment-resistant, left-sided ulcerative colitis (UC). Mayo Clin Proc 1996;71:431-6. 34.Sendid B, Colombel JF, Jacquinot PM, et al. Specific antibody response to oligomannosidic epitopes in Crohn's disease. Clin Diagn Lab Immunol 1996;32:219-26. 35.Ruemmele FM, Dubinsky M, Targan S, Barun J, Seidman E. Specificity of a new serologic test for pediatric Crohn's disease. J Pediatr Gastroenterol Nutr 1997;25:A448 36.Vasiliauskas E, Plevy SE, Landers CJ, et al. Perinuclear cytoplasmic antibodies (pANCA) in patients with Crohn's disease define a clinical subgroup. Gastroenterology 1996;110:18 10-9. 37.Sartor RB. Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am 1995;24(3):475-507. 38.Sartor RB. Cytokines in intestinal inflammation: pathophysiological and clinical considerations. Gastroenterology 1994;106:533-9. 39.Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology 1995; 109:1344-67. 40.Sartor RB. Cytokine regulation of experimental intestinal inflammation in genetically engineered and T-lymphocyte reconstituted rodents. Aliment Pharmacol Ther 1996;10(suppl 2):36-42. 41.Sartor RB, Rath HC, Lichtman SN, van Tol EA. Animal models of intestinal and joint inflammation. Baillieres Clin Rheum 1996;10: 55-76. 42.Ekbom A, Adami HO, Helmick CG, Jonzon A, Zack MM. Perinatal risk factors for inflammatory bowel disease: a case-control study. Am J Epidemiol 1990;132:1111-9. 43.Whorwell PJ, Holdstock G, Whorwell GM, Wright R. Bottle feeding, early gastroenteritis, and inflammatory bowel disease. BMJ 1979;1:382. 44.Wurzelman JI, Lyles CM, Sandler RS. Childhood infections and the risk of inflammatory bowel disease. Dig Dis Sci 1994;39:555-60. 45.Subhani J, Montgomery SM, Thompson N, Ebrahim S, Wakefield AJ, Pounder RE. Childhood risk factors for inflammatory bowel disease using a twin case control method. Gut 1996;39:A59. 46.Ekbom A, Wakefield AJ, Zack M, Adami HO. Perinatal measles infection and subsequent Crohn's disease. Lancet 1994;344:508-10. 47.Ekbom A, Daszak P, Kraaz W, Wakefield AJ. Crohn's disease following in-utero measles virus exposure. Lancet 1996;348: 515-7. 48.Lewin J, Dhillon AP, Sim R, Mazure G, Pounder RE, Wakefield AJ. Persistent measles virus infection of the intestine: confirmation by immunogold electron microscopy. Gut 1995;36:564-69. 49.Wakefield AJ, Pittilo RM, Sim R, et al. Evidence of persistent measles virus infection in Crohn's disease. J Med Virol 1993;39: 345-53. 50.Thompson NP, Montgomery SM, Pounder RE, Wakefield AJ. Is measles vaccination a risk factor for inflammatory bowel disease? Lancet 1995;345:1071-3. 51.Feeney M, Clegg A, Winwood P, Snook J. A case-control study of measles vaccination and inflammatory bowel disease. Lancet 1997;350:764-6. 52.Theofilopoulos AN. The basis of autoimmunity: part 1. mechanisms of aberrant self-recognition. Immunol Today 1995;16:90-8. 53.Snook J. Are the inflammatory bowel diseases autoimmune disorders? Gut 1990;31:961-3. 54.McFarland HF. Complexities in the treatment of autoimmune disease. Science 1996;274:2037-8. 55.Ina K, Binion DG, West GA, Dobrea GM, Fiocchi C. Crohn's disease (CD) mucosal T-cells are resistant to apoptosis. Gastroenterology 1995;108:A841. 56.Seidman EG, Hanson DG, Walker WA. Increased permeability to polyethylene glycol 4000 in rabbits with experimental colitis. Gastroenterology 1986;90:120-6. 57.Bjarnason I, Macpherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology 1995;108:1566-81. 58.Hollander D. The intestinal permeability barrier: a hypothesis as to its regulation and involvement in Crohn's disease. Scand J Gastroenterol 1992;27:721-6. 59.Hollander D, Vadheim CM, Brettholz E, Peterson GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients with Crohn's disease and their relatives: a possible etiologic factor. Ann Intern Med 1986;105:883-5. 60.Katz KD, Hollander D, Vadheim CM, et al. Intestinal permeability in patients with Crohn's diesase and their healthy relatives. Gastroenterology 1989;97:927-31. 61.May GR, Sutherland LR, Meddings JB. Is small intestinal permeability really increased in relative of patients with Crohn's disease? Gastroenterology 1993; 104; 1627-32. 62.Howden CW, Gillanders 1, Morris AJ, Duncan A, Danesh B, Russell RI. Intestinal permeability in patients with Crohn's disease and their first-degree relatives. Am J Gastroenterol 1994;89: 1175-6. 63.Ainsworth M, Eriksen J, Rasmussen JW. Intestinal permeability of 51Cr-labelled ethylenediaminetetraacetic acid in patients with Crohn's disease and their healthy relatives. Scand J Gastroenterol 1989;24:993-8. 64.Ruttenburg D, Young GO, Wright JP, Isaacs S. PEG-400 excretion in patients with Crohn's disease, their first-degree relatives, and healthy volunteers. Dig Dis Sci 1992;37:705-8. 65.Teahon K, Smethurst P, Levi AJ, Menzies IS, Bjarnason I. Intestinal permeability in patients with Crohn's disease and their first degree relatives. Gut 1992;33:320-3. Session 2. Initial Maintenance Therapy (Relapse Prevention) and Therapy of Steroid Resistance and Dependence Harland Winter Children's Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A. Introduction This session focused on the prevention of relapse in ulcerative colitis and Crohn's disease and the treatment for steroid-resistant Crohn's disease. The prevention of relapse with ulcerative colitis and Crohn's disease has not been studied extensively in children, but experience in the adult population, especially in ulcerative colitis, permits us to extrapolate to the pediatric patient. Clinical experience over the past decade suggests that the same therapeutic strategies used in adults have been applied to children. In contrast, the experience with immunomodulatory treatment for steroid-resistant Crohn's disease has been evaluated more extensively in the adult population. Although studies are beginning in the pediatric population, the number of children evaluated with medications such as methotrexate does not permit us to make evidence-based decisions. Immunomodulatory, nutritional, and surgical therapies all appear to have a role in the management of the child with steroid-dependent Crohn's disease. Harland Winter, M.D., from Children's Hospital and Harvard Medical School, Boston, Massachusetts, organized and moderated this session. Discussants were Mel Heyman, M.D., from the University of California, San Francisco, California; Robert Squires, M.D., from Children's Medical Center and the University of Texas Southwest Medical Center, Dallas, Texas; M. Susan Moyer, M.D., from Yale-New Haven Hospital and Yale University School of Medicine, New Haven, Connecticut; George Ferry, M.D., from Texas Children's Hospital and Baylor College of Medicine, Houston, Texas; Susan S. Baker, M.D., Ph.D., from Children's Hospital and Medical University of South Carolina, Charleston, South Carolina; and Anne Griffiths, M.D., from the Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada. Therapy for Prevention of Relapse of Ulcerative Colitis Dr. Heyman reviewed the efficacy of sulfasalazine and 5-aminosalicylic acid (5-ASA) preparations. Beginning in the 1970s, sulfasalazine was used to maintain remission in ulcerative colitis. Dissanayake and Truelove reported that 2.0 g/day of sulfasalazine was 4 times as effective as placebo in maintaining remission in adults with ulcerative colitis (relapse rate of 12% for sulfasalazine vs. 55% for placebo; 1). Seven years later, Azad Khan et al. (2) reported that 2.0 g/day of sulfasalazine was the optimal dose for relapse prevention (2). In adults with frequent episodes of relapse, 40 mg every other day of prednisolone was also found to be more effective than placebo in maintaining remission over 3 months (3). As newer preparations of 5-ASA became available, comparison with sulfasalazine seemed to yield similar results. A meta-analysis of 11 randomized controlled trials, involving 1,153 patients, showed no difference between any of 5-ASA preparations and sulfasalazine in relapse prevention. Adverse effects were noted in 17-18% of patients, and 8% of 5-ASA-treated and 9% of sulfasalazine-treated patients were discontinued because of adverse effects from the medication (4). The risk of relapse in children with ulcerative colitis who were receiving maintenance therapy was assessed in a retrospective chart review by Hyams et al. (5). Although treatment was not standardized, remission was induced in 80-90% of patients within 6 months. Although relapse in the first year was dependent on the severity of disease at the time of presentation, overall, 55% remained free of symptoms. The relation of extraintestinal factors such as stress, dietary fiber, systemic manifestations, or seasonal periodicity to relapse was evaluated in the adult population, but consistent conclusions have not been established (6,7). Sulfasalazine and 5-ASA preparations appear to be equally effective at comparable doses for relapse prevention in children with ulcerative colitis. Between 20 and 50% of patients will experience symptoms of relapse annually. Other therapeutic strategies for relapse prevention, such as disodium cromoglycate, hydrocortisone retention enemas, and prednisone (15 mg/day) have not been critically evaluated in children, but do not appear to be effective in the adult population. Therapy for Prevention of Relapse of Crohn's Disease After Medically Induced Remission Dr. Robert Squires reviewed prevention of relapse after a medically induced remission. Treatment efficacy is difficult to assess because of differences in disease location, therapeutic regimens, and definition of remission. Although the therapy used to induce remission is not always controlled in clinical trials, mesalamine, azathioprine/6-mercaptopurine, corticosteroids, and dietary therapy have been evaluated as interventions to prevent relapse. In adults with small bowel or ileal disease, mesalamine, when initiated at the time of remission, seems to prolong remission, especially in those patients treated medically, with high Crohn's Disease Activity Index (CDAI), and leukocyte count >9,000 (8). Patients older than 30 years may respond better than younger individuals (9). The only study in the pediatric population demonstrated a benefit in children with active small bowel disease who were treated with 30 mg/kg/day of mesalamine (Pentasa) in an open-label trial followed by a prospective, double-blind, placebo-controlled trial of 50 mg/ kg/day (maximal dose, 3 g/day) of mesalamine (10). Azathioprine and 6-mercaptopurine (6-MP) have been used as steroid-sparing agents to prevent relapse (11). Although these drugs should have similar biologic effects, azathioprine has been used more often in the pediatric population. A dose of 1.5 mg/kg of 6-MP is equivalent to a dose of 2.7 mg/kg of azathioprine. Adult patients with Crohn's disease who are off corticosteroids and in remission while maintained on azathioprine (2.0 mg/kg) have a lower rate of relapse than those patients who discontinue therapy (12). Meta-analysis suggests that both medications are effective in maintaining remission, but not without the potential side effects of leukopenia, pancreatitis, and nausea (13). In children, studies with azathioprine and 6-MP have been retrospective but suggest a steroid-sparing effect for patients with active disease as well as with disease in remission (14). After induction of remission with prednisone, 25 mg of prednisone given on alternate days in conjunction with sulfasalazine was effective at maintaining remission in more than half of the adult patients (15). However, cosmetic side effects are a significant factor in patient acceptance, especially in the pediatric population. For these reasons, a rapidly metabolized corticosteroid, budesonide, is being studied as a steroid-sparing agent in maintaining remission (16). Trials are planned for the pediatric population for whom such an agent would be particularly beneficial, especially if the therapy did not delay growth. Dietary therapy may be beneficial in maintaining remission and is appealing because of the potential for few side effects (17). Oligopeptide formulas and omega-3 fatty acids (fish oil) have been the most extensively studied. Seidman et al. (18) reported a trend toward fewer relapses when an oligopeptide formula was compared with alternate-day prednisone (0.33 mg/kg q.o.d.). Additionally, patients who went into remission with exclusive enteral nutrition had prolonged remission and improved linear growth if nighttime nasogastric feedings with an oligopeptide- or amino acid-based formula were continued (19). Omega-3 fatty acids reduce the production of leukotriene B4 and thromboxane A2, inhibit the synthesis of cytokines, and scavenge free radicals. Enteric-coated preparations containing 2.7 g of ω-3 fatty acids reduced relapse rates (odds ratio, 4.2) in adults, as measured by the CDAI when compared with placebo (20). However, similar studies have not been completed in children. Therapy for Prevention of Relapse of Crohn's Disease After Surgically Induced Remission Dr. M. Susan Moyer discussed recurrence of Crohn's disease after surgical resection. If the assessment is based on clinical symptoms, the rate is somewhat lower than the rate that is determined by endoscopic evaluation (21). Comparison of studies is hampered because of different methods of assessing outcome, lack of standardization of the location of the resected bowel, variations in time to initiation of therapy, and differences in type of medication, dose, and length of administration. Rutgeerts et al. (22) used metronidazole to determine whether therapy was better than placebo at preventing recurrence after ileocolectomy. At 1 year, clinical recurrence was much less in the treatment group; endoscopic improvement was not statistically significant. After 3 years, there was no significant difference in either endoscopic or clinical recurrence (23). Studies with 5-ASA to prevent recurrence after resection revealed optimistic results (24). The 3-year actuarial risk of recurrence was 26% in the mesalamine treatment group compared with 45% in the placebo group. Patients with disease limited to the small intestine had a slightly poorer response to treatment (25). Unfortunately, there are no controlled trials in children who have had resections. This gap in knowledge is especially relevant for the pediatric population because there may be an increased frequency of surgery and postoperative recurrence in patients younger than 20 years. This observation may be related to the site of disease, which in children more commonly includes both the small bowel and colon than in adults (26). Clinical practice now is guided by extrapolation from the adult trials. Therapy in Steroid-Resistant or Steroid-Dependent Crohn's Disease The Role of Immunomodulatory Therapy Dr. George Ferry asserted that avoiding chronic steroid use is especially important in children with IBD, but many children remain steroid dependent. The immunemodulating drugs may be the next choice in patients who fail to respond to corticosteroids or who are steroid dependent. Azathioprine/6-MP, cyclosporine, and methotrexate have been used in both pediatric and adult patients, and the results of studies are summarized in Tables 1–3. Table 1. Summary of published data for azathioprine/6-MP Open in new tab Table 1. Summary of published data for azathioprine/6-MP Open in new tab Table 2. Summary of published data for cyclosporine Open in new tab Table 2. Summary of published data for cyclosporine Open in new tab Table 3. Summary of published data for methotrexate Open in new tab Table 3. Summary of published data for methotrexate Open in new tab Azathioprine/6-MP have been used for the past decade, and the published experience exceeds 600 adult patients and 80 children (Table 1). Suggested indications are (a) one or more relapses when corticosteroids are reduced or stopped; (b) inability to reduce the dose of corticosteroids; (c) failure to respond to corticosteroids (with or without 5-ASA); (d) fistulae unresponsive to corticosteroids and metronidazole; and (e) perianal disease unresponsive to other therapy. A commonly used dose for 6-MP is 1.5 mg/kg/day, and for azathioprine, the dose is 2.0 mg/kg/day. Maximal benefit is usually noted between 3 and 6 months after starting therapy. Experience in adults suggests that increasing the dose to produce mild leukopenia will improve results and shorten the time to remission. Leukopenia can occur in >25% of patients, even with low-dose therapy. Pancreatitis and elevated liver-function tests should be considered potential complications. Although complications such as lymphoma are unlikely, careful monitoring should be part of standard therapy. The ability to metabolize the drug should be evaluated in patients considered for intravenous therapy and for those individuals in whom complications develop. For the pediatric patient, knowledge is needed about (a) long-term effects and risk of malignancy and infection; (b) the role of leukopenia in selecting a proper dose; (c) how long to continue therapy after an initial response; and (d) the role of concomitant corticosteroid therapy. The response to cyclosporine may be rapid, but longterm efficacy has often not been shown (Table 2). Potential indications for using cyclosporine to treat Crohn's disease include chronic active disease unresponsive to corticosteroids or severe perianal and fistulous disease. The most frequent dose of cyclosporine used is 4-5 mg/ kg/day i.v. or 4-10 mg/kg/day orally; therapy must be individualized to adjust to trough drug levels. Adverse effects include hypertension, hirsutism, renal dysfunction, tremors, depression, and serious infections. Methotrexate use in children with Crohn's disease has primarily been reserved for patients who have an adverse reaction to or have failed to respond to azathioprine/6-MP. Although the experience in pediatric rheumatology is extensive and with fewer side effects than predicted, knowledge about the use in children with inflammatory bowel disease is minimal (Table 3). The most frequently used dose is 0.5 mg/kg once weekly or 10 mg/m2 once weekly. For older children, 12.5-25 mg is the most common dose, and subcutaneous or intramuscular dosing seems to improve the response and to decrease side effects. A response is usually seen within the first few weeks of therapy. Hepatic inflammation or fibrosis, pulmonary fibrosis, nausea, diarrhea, oral ulcers, hypersensitivity, pneumonitis, leukopenia, rash, and optic neuritis have been reported. The Role of Nutrition Therapy Susan Baker reviewed the literature of nutrition therapy. Data support the hypothesis that enteral or parenteral nutrition therapy can induce a remission in patients with active Crohn's disease. Although nutrition is a safe therapy, steroids and sulfasalazine are superior when nutrition is used alone to induce remission (27). The impact of long-term corticosteroids on nutritional status is well established in the growing child. Deficiencies in vitamins, zinc, minerals, energy, and protein occur in children with Crohn's disease but are aggravated in those patients requiring chronic steroid use. Without attention to proper nutrition, metabolic problems such as poor bone mineralization, fractures, and poor growth may occur. Although the importance of nutrition to maintain normal growth and development has been studied in the pediatric population (28,29), the role of nutrition as an immune modulator that can alter the course of Crohn's disease in children who are dependent on corticosteroids remains to be tested. The Role of Surgical Therapy Dr. Anne Griffiths emphasized that surgical therapy is not curative for patients with Crohn's disease. Based on return of symptoms and radiologic evidence of disease, the overall recurrence rate in children and adolescents undergoing their first resection is 50% by 5 years. Factors influencing recurrence have not been consistently identified. In some studies, patients with extensive ileocolonic involvement had earlier recurrences (30). Preoperative duration of disease, especially in the adult population, did not correlate with time to recurrence (31), but in children, shorter periods of preoperative illness seemed to correlate with later recrudescence of active disease. Limited surgical intervention before or during early puberty may result in substantial improvement in height velocity in children with growth retardation (32); however, early recurrence of disease activity can impair the potential benefit of a surgically induced remission (33). Referral for intestinal resection should not be made solely on the basis of steroid resistance or steroid dependence, but rather on the extent and nature and urgency of the Crohn's disease; in contrast to many other complications of Crohn's disease, fulminant colitis and obstructing strictures often require surgical resection. When growth is impaired in a prepubertal or early adolescent child with localized, stenotic, nonprogressive disease, surgical intervention should be considered. Perspective The data and the discussion that ensued supported the conclusion that in children with ulcerative colitis, sulfasalazine and 5-ASA preparations are effective at relapse prevention, but that other forms of therapy must be studied in children who do not respond to standard therapy. In children with Crohn's disease, data are needed about the best interventions to maintain medically or surgically induced remission. Although immunomodulatory therapies appear to be the most promising interventions, prospective randomized studies must be completed in the pediatric population adequately to evaluate these medications in children. The presence of a developing immune system and impact of the disease treatment options on growth provide a specialized environment in children. These unique aspects limit the direct application of efficacy studies performed in adults to therapy in children. Clinical trials in children should provide guidelines for appropriate therapy. References 1.Dissanayake AS, Truelove SC. A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulphazalazine (Salazopyrin). Gut 1973;14:923-6. 2.Azad Khan AK, Howes DT, Pires J, Truelove SC. Optimum dose of sulphasalazine for maintenance treatment in ulcerative colitis. Gut 1980;21:232-40. 3.Powell-Tuck J, Bown RL, Chambers TJ, Lennaard-Jones JE. A controlled trial of 5-aminosalicylic acid in the treatment of ulcerative colitis. Digestion 1981;22:263-70. 4.Sutherland LR, May GR, Shafer EA. Sulfasalazine revisited: a meta-analysis of 5-aminoslicylic acid in the treatment of ulcerative colitis. Ann Intern Med 1993;118:540-9. 5.Hyams JS, Davis P, Grancher K, Lerer T, Justinich CJ, Markowitz J. Clinical outcome of ulcerative colitis in children. J Pediatr 1996; 129:81-8. 6.Leo S, Leandro G, Di Matteo G, Caruso ML, Lorusso D. Ulcerative colitis in remission: it is possible to predict the risk of relapse. Digestion 1989;44:217-21. 7.Von Wietersheim J, Kohler T, Feiereis H. Relapse-precipitation life events and feelings in patients with inflammatory bowel disease. Psychother Psychosomat 1992;58:103-12. 8.Modigliani R, Colombel JF, Dupas JL, et al. and groupe d estudes therapeutizues dis affections inflammatioires digestives. Mesalamine in Crohn's disease with steriod-induced remissin: effect on steroid withdrawal and remission maintenance. Gastroenterology 1996;110:688-93. 9.Arber N, Odes HS, Fireman Z, et al. A controlled double blind multicenter study of the effectiveness of 5-aminosalicylic acid in patients with Crohn's disease in remission. J Clin Gastroenterol 1995;20:203-6. 10.Griffiths A, Koletzko S, Sylvester F, Marcon M, Sherman P. Slowrelease 5-aminosalicylic acid therapy in children with small intestinal Crohn's disease. J Pediatr Gastroenterol Nutr 1993;17:186-92. 11.Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz GL. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989;111: 641-9. 12.Bouhnik Y, Lemann M, Maary JY, et al. Long term follow up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet 1996;347:215-9. 13.Pearson DC, Mar GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn's disease: a meta-analysis. Ann Intern Med 1995;122:132-42. 14.Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr 1990;117: 809-14. 15.Bello C, Goldstein F, Thornton JJ. Alternate day prednisone treatment and treatment maintenance in Crohn's disease. Am J Gastroenterol 1991;86:460-6. 16.Lofberg R, Rutgeerts P, Malchow H, et al. Budesonide prolongs time to relapse in ileal and ileocecal Crohn's disease: a placebo controlled one year study. Gut 1996;39:82-6. 17.Polk DB, Hattner JAT, Kerner JA. Improved growth and disease activity after intermittent administration of a defined formula diet in children with Crohn's disease. J Parenter Enter Nutr 1992;16: 499-504. 18.Seidman E, Jones A, Issenman R, Griffiths A. Relapse prevention/ growth enhancement in pediatric Crohn's disease: multicenter randomized controlled trial of intermittent enteral nutrition versus alternate day prednisone. J Pediatr Gastroenterol Nutr 1996;23: 344A. 19.Wilchanski M, Sherman P, Pencharz P, Davis L, Corey M, Griffiths A. Supplementary enteral nutrition maintains remission in paediatric Crohn's disease. Gut 1996;38:543-8. 20.Belluzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med 1996;334:1557-60. 21.Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn's disease. Gastroenterology 1990;99:950-63. 22.Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn's disease after ileal resection. Gastroenterology 1995;108:1617-21. 23.Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole treatment for prevention of Crohn's disease after ileal resection. Gastroenterology 1995;108:1617-21. 24.Brignola C, Cottone M, Pera A, et al. Mesalamine in the prevention of endoscopic recurrence after intestinal resection for Crohn's disease. Gastroenterology 1995;109:345-9. 25.McLeod RS, Wolff BG, Steinhart AH, et al. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn's disease. Gastroenterology 1995;109:404-13. 26.Polito JM II, Childs B, Mellits ED, Tokayer AZ, Harris ML, Bayless TM. Crohn's disease: Influence of age at diagnosis on site and clinical type of disease. Gastroenterology 1996;111:580-6. 27.Griffiths AM, Ohlsson A, Sherman PM, Sutherland LR. Metaanalysis of enteral nutrition as a primary treatment of active Crohn's disease. Gastroenterology 1995;108: 1056-67. 28.Motil KJ, Grand RJ, Maletskos CJ, Young VR. The effect of disease, drug, and diet on whole protein metabolism in adolescents with Crohn's disease and growth failure. J Pediatr 1982;101:345-51. 29.Motil KJ, Grand RJ, Davis-Kraft L, Ferlic LL, Smith EO. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993;105:681-91. 30.Griffiths AM, Wesson DE, Shandling B, Corey M, Sherman PM. Factors influencing postoperative recurrence of Crohn's disease in childhood. Gut 1991;32:491-5. 31.Shivananda S, Hordijk ML, Pena AS, Mayberry JF. Crohn's disease: risk of recurrence and reoperation in a defined population. Gut 1989;30:990-5. 32.Walker-Smith JA. Management of growth failure in Crohn's disease. Arch Dis Child 1996;75:352-4. 33.Homer DR, Grand RJ, Colodny AH. Growth, course and prognosis after surgery for Crohn's disease in childhood. Pediatrics 1977; 59:717-25. Session 3. Perianal Disease, Growth Failure, and Quality of Life Richard B. Colletti University of Vermont, Burlington, Vermont, U.S.A. Introduction The purpose of this panel presentation was to discuss controversial issues in the management of perianal disease in Crohn's disease, growth failure in Crohn's disease, and assessment of health-related quality of life in inflammatory bowel disease. Richard B. Colletti, M.D., University of Vermont College of Medicine, Burlington, Vermont, organized and moderated this session. Discussants were James Markowitz, M.D., from North Shore University Hospital, Manhasset, New York; Anne M. Griffiths, M.D., from the Hospital for Sick Children and The University of Toronto, Toronto, Ontario, Canada; and Sylviane Forget, M.D., from McMaster Medical Center, Hamilton, Ontario, Canada. Perianal Disease in Children with Crohn's Disease Dr. James Markowitz discussed perianal disease in children with Crohn's disease. The prevalence of perianal disease in patients evaluated at tertiary care centers is 14-62% (1–6). The types of perianal lesions include anal fissures and tags, fistulas, abscesses, and highly destructive perianal disease, including cavitating ulceration. There have been no controlled trials of treatment of perianal disease in children. However, there have been reports of uncontrolled clinical experience. Treatment of anal fissure, fistula, and abscess with metronidazole was associated with a good response in 70-75% in one study (4). In another study, when 6-mercaptopurine was administered for intractable intestinal symptoms, 63% of patients with perianal disease had healing of fistula or abscess (7). In a report (5) of six children with highly destructive lesions, only two improved despite medical treatment with metronidazole, corticosteroids, cyclosporine, or 6-mercaptopurine, singly or in combination; three improved after surgical treatment (colostomy or proctocolectomy). In another report (6), three of four pediatric patients with mild perianal disease improved with medical therapy. The experience with moderate to severe disease was much less favorable. The experience with treatment of perianal disease in adults was summarized (8,9). Metronidazole therapy is associated with a high rate of improvement (85%), but also a high rate of relapse (70%). Recent reports showed similar results with ciprofloxacin (10,11). Cyclosporine was effective in 70% of reported cases, but relapses occurred (12,13). Treatment of fistulas with 6-mercaptopurine or azathioprine produced a good response in 54% of adult patients, compared with 21% of placebo controls (14). Two of four patients treated with methotrexate to control active intestinal disease had healing of fistulas (15). Treatment with an elemental diet produced healing of fistulas in 67-85%, but there was a high relapse rate (16,17). In one study, hyperbaric oxygen therapy produced complete healing in 70%, with no recurrence after 18 months (18). Surgical treatment of perianal disease included fistulotomy for simple or low fistulas, fistulotomy with seton insertion for complex or high fistulas, incision and drainage of abscesses, and a diverting stoma or proctocolectomy for highly destructive lesions. Growth Impairment in Crohn's Disease Dr. Anne M. Griffiths discussed growth impairment in Crohn's disease. The particular challenge and responsibility of managing Crohn's disease in a child, beyond controlling intestinal symptoms, is to optimize growth. Growth is an important indicator of control of disease activity and success of therapy. Normal growth proceeds at a steady rate, influenced by hormones, nutrition, and genetic potential. Growth can be monitored by the linear growth chart, pubertal staging, and bone age. Inflammatory disease can interfere with the very rapid accumulation of lean body mass that normally occurs during adolescence, particularly in boys, whose growth spurt normally comes later, lasts longer, and is of greater magnitude. Crohn's disease commonly causes impairment of linear growth before and after diagnosis. Height at maturity is often compromised. Height velocity is the most sensitive parameter by which to diagnose impaired growth and to follow the effects of therapy on growth. A decrease in height velocity before the onset of intestinal symptoms was reported in 46% of patients at Tanner stage 1 or 2 (19); it was also seen in 32% of children at the time of diagnosis in a population-based Swedish study (20). The greater the height deficit is at diagnosis, the greater are the demands for catch-up growth. After diagnosis, impairment of height velocity for ≥1 or 2 years has occurred in 50-65% of children. Many children under treatment for Crohn's disease will increase their height-for-age standard deviation score (SDS), but as a group, they remain below average. In one study, 37% of 38 children with Crohn's disease at a tertiary care center who were followed up into adulthood were permanently shorter than predicted (21). In another study (22), children already significantly stunted at the time of diagnosis had a worse prognosis; 59% of those followed up to maturity failed to reach the third percentile for adult height. Chronic undernutrition has long been recognized as a major factor in growth impairment (23). This is reflected in low serum levels of insulin-like growth factor-1 (24). Inadequate caloric intake, due to disease-related anorexia and exacerbation of abdominal cramps with eating, is the primary cause of the caloric inadequacy. Resting energy expenditure among patients with Crohn's disease is usually normal, without the compensatory reduction expected for such undernutrition. Malabsorption and increased caloric requirements are less important factors contributing to poor growth. The growth-retarding effect of chronic inflammation is still poorly defined. It is postulated that inflammatory mediators, such as the macrophage product tumor necrosis factor-α (TNF-α) and interleukin 1 (IL-1) secreted from the inflamed gut, may act to suppress growth (25). The combination of optimal treatment of intestinal inflammation and the provision of adequate nutrition are of paramount importance in the management of young patients. Daily treatment with corticosteroids can effectively reduce inflammation but will prevent linear growth. Low-dose alternate-day corticosteroids do not impede linear growth but may not control the inflammatory process well enough to facilitate normal growth. A randomized placebo-controlled trial of alternate-day prednisone in prevention of relapse is in progress. The beneficial effects of exclusive or supplementary enteral nutrition on linear growth are well documented (26–28). The efficacy of exclusive enteral nutrition as primary therapy of active Crohn's disease is controversial; enteral nutrition may be of therapeutic benefit, even if efficacy does not equal that of corticosteroid treatment. In Phase II of the Canadian Paediatric Collaborative trial, linear growth was better and the rate of clinical relapse lower with cyclic enteral nutrition in comparison with alternate-day prednisone (29). When growth is significantly impaired in a young patient with localized stenotic disease, an early operative approach should be considered. Quality of Life Dr. Sylviane Forget discussed issues of health-related quality of life (HRQOL) in children with inflammatory bowel disease. HRQOL is defined as the functional effect of an illness and its consequent therapy on a patient, as perceived by the patient. The four broad domains of HRQOL include physical and occupational function, emotional state, social interaction, and somatic sensation (30). When applied to pediatric populations, the concept should also encompass attributes such as communication skills, learning and schooling ability, and rate of achievement of developmental milestones (31,32). Three types of instruments are available to assess HRQOL: global assessment, utility measures, and generic measures. To be clinically useful, instruments must be valid and reliable, as well as able to detect small but clinically important changes. Disease-specific indices are generally considered to be more responsive than their generic counterparts. HRQOL assessment allows us to describe the full impact of disease on psychological and social functions, to identify individual needs, to recognize subgroup differences, to improve the selection of therapies, and to support decisions on resource allocation. In clinical research, it complements other biomedical indices in outlining the natural history of the disease and long-term prognosis, and it constitutes a valid and reliable method of measuring outcomes in clinical trials. Juvenile-onset inflammatory bowel disease significantly affects the emotional status, social function, education, and career prospects of patients (33,34). HRQOL is influenced by disease-related factors, such as the need for surgery or the presence of growth failure, as well as non-disease-related factors, such as poor family function. Disease-specific instruments, best suited for measuring outcome in inflammatory bowel disease, should be tailored to the specific needs of children and, once validated, should be included as an essential component of assessing treatment in clinical trials (35). Future Directions To improve the management of perianal disease, it will be necessary to perform randomized controlled trials in children and adolescents. A study of the value of magnetic resonance imaging in determining the extent of fistulous disease in children also appears warranted. The future management of growth failure in inflammatory bowel disease should include better tools for earlier recognition of disease, greater use of nutritional therapies, and more effective treatments of intestinal inflammation that do not impair growth. We look toward work in progress for the development of a standardized, validated, reliable pediatric inflammatory bowel disease quality-oflife measurement tool, for clinical research and, in an abbreviated form, for clinical care. References 1.Hamilton JE, Bruce GA, Abdourhaman M, Gall DB. Inflammatory bowel disease in children and adolescents. In: Barness L, ed. Advances in Pediatrics. Vol 26. Chicago: Yearbook Medical Publishers, 1979:311-41. 2.Markowitz J, Daum F, Aiges H, Kahn E, Silverberg M, Fisher SE. Perianal disease in children and adolescents with Crohn's disease. Gastroenterology 1984;86:829-33. 3.Michener WM, Caulfield M, Wyllie R, Farmer RG. Management of inflammatory bowel disease: 30 years of observations. Cleveland Clin J Med 1990;57:685-91. 4.Palder SB, Shandling B, Bilik R, Griffiths AM, Sherman P. Perianal complications of pediatric Crohn's disease. J Pediatr Surg 1991;26:513-5. 5.Markowitz J, Grancher K, Rosa J, Simpser E, Aiges H, Daum F. Highly destructive perianal disease in children with Crohn's disease. J Pediatr Gastroenterol Nutr 1995;21:149-53. 6.Tolia V. Perianal Crohn's disease in children and adolescents. Am J Gastroenterol 1996;91:922-6. 7.Markowitz J, Rosa J, Grancher K, Aiges H, Daum F. Long-term 6 mercaptopurine treatment in adolescents with Crohn's disease. Gastroenterology 1990;99:1347-51. 8.Bernstein LH, Frank MS, Brandt LJ, Boley SJ. Healing of perineal Crohn's disease with metronidazole. Gastroenterology 1980;79: 357-65. 9.Brandt LJ, Bernstein L, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology 1982;83:383-7. 10.Wolf JL. Ciprofloxacin may be useful in Crohn's disease. Gastroenterology 1990;98:A212. 11.Turenen U, Farkkila M, Valtonen V, Seppala K. Long-term outcome of ciprofloxacin treatment in severe perianal or fistulous Crohn's disease. Gastroenterology 1993; 104:A793. 12.Hanauer SB, Smith MB. Rapid closure of Crohn's disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993;88:646-9. 13.Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn's disease. Dig Dis Sci 1994;39:374-80. 14.Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease: a meta-analysis. Ann Intern Med 1995;122:132-42. 15.Lemann M, Chamiot-Prieur C, Mesnard B, et al. Methotrexate for the treatment of refractory Crohn's disease. Aliment Pharmacol Ther 1996;10:309-14. 16.Calam J, Crooks PE, Walker RJ. Elemental diets in the management of Crohn's perianal fistulae. J Parenter Enter Nutr 1980;4:4-8. 17.Teahon K, Bjarnason I, Pearson M, Levi AJ. Ten years experience with an elemental diet in the management of Crohn's disease. Gut 1990;31:1133-7. 18.Lavy A, Weisz G, Adir Y, Ramon Y, Melamed Y, Eidelman S. Hyperbaric oxygen for perianal Crohn's disease. J Clin Gastroenterol 1994;19:202-5. 19.Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn's disease. Gastroenterology 1988;95:1423-527. 20.Hildebrand H, Karlberg J, Kristiansson B. Longitudinal growth in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1994;18:165-73. 21.Markowitz J, Grancher K, Rosa J, Aiges H, Daum F. Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993:16:373-80. 22.Griffiths AM, Nguyen P, Smith C, MacMillan H, Sherman PM. Growth and clinical course of children with Crohn's disease. Gut 1993;34:939-43. 23.Kelts DG, Grand RJ, Shen G, Watkins JB, Werlin SL, Boehme C. Nutritional basis of growth failure in children and adolescents with Crohn's disease. Gastroenterology 1979;76:720-7. 24.Thomas AG, Holly JM, Taylor F, Miller V. Insulin like growth factor-I, insulin like growth factor binding protein-1, and insulin in childhood Crohn's disease. Gut 1993;34:944-7. 25.Murch SH, Lamkin VA, Savage MO, Walker-Smith JA, MacDonald TT. Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease. Gut 1991;32: 913-7. 26.Aiges H, Markowitz J, Rosa J, Daum F. Home nocturnal supplemental nasogastric feedings in growth-retarded adolescents with Crohn's disease. Gastroenterology 1989;97:905-10. 27.Belli DC, Seidman E, Bouthillier L, et al. Chronic intermittent elemental diet improves growth failure in children with Crohn's disease. Gastroenterology 1988;94:603-10. 28.Griffiths AM, Ohlsson A, Sherman PM, Sutherland LR. Metaanalysis of enteral nutrition as a primary treatment of active Crohn' disease. Gastroenterology 1995;108: 1056-67. 29.Seidman E, Jones A, Issenman R, Griffiths A. Relapse prevention/ growth enhancement in pediatric Crohn's disease: multicenter randomized controlled trial of intermittent enteral nutrition versus alternate day prednisone. J Pediatr Gastroenterol Nutr 1996;23: A344. 30.Spilker B. Quality of life and pharmacoeconomics in clinical trials. 2nd ed. Philadelphia: Lippincott-Raven Publishers, 1996. 31.Cadman D, Goldsmith C, Torrance GW. A methodology for utilitybased health status index for Ontario children: final report to the Ontario Ministry of Health. Hamilton: McMaster University, 1986. 32.Starfield B. Child health status and outcome of care: a commentary on measuring the impact of medical care on children. J Chron Dis 1987;40:109S-115. 33.Ferguson A, Sedgwick DM, Drummond J. Morbidity of juvenile onset inflammatory bowel disease: effects on education and employment in early adult life. Gut 1994;35:65-8. 34.Orkin BA, Telander RL, Wolff BG, Perreault J, Ilstrup DM. The surgical management of children with ulcerative colitis: the old vs. the new. Dis Colon Rectum 1990;33:947-55. 35.Forget S, Issenman RM, Gold N, Irvine EJ. Assessment of functional status in children and adolescents with inflammatory bowel disease. Gastroenterology 1997;112:A974. Session 4. Malignancy and Aneuploidy: Prevention and Early Detection Barbara Kirschner University of Chicago Children's Hospital, Chicago, Illinois, U.S.A. Introduction It is reasonable to question whether the observation in 1971, by Devroede et al. (1), relating the risk of colon cancer to extent and duration of disease, might now be modified by the use of a wider range of drugs, including immunosuppressive agents in use. In addition, there was an expectation that maximizing therapy might prevent the progression from low-grade dysplasia (LGD) to highgrade dysplasia (HGD). This concept was supported by observations of Langholz et al. (2), who in 1992 showed that the incidence of colon cancer was no greater after 25 years for patients with ulcerative colitis (UC) with retained colons (3.5%) than in patients without UC in the general Danish population (3.5%). However, Ekbom et al. (3,4) reported that in the 1990s, there was still an increased risk for colon cancer in patients with longstanding UC (35 years). The risk was 40% for those diagnosed before age 15 years and 30% for those diagnosed later in life. These observations have now been extended to show that without colectomy, 50% of patients diagnosed with pancolitis younger than 14 years will develop colon cancer by age 50 years (Ekbom et al., unpublished data). Thus the goal of this session was to discuss how to better determine who should undergo colectomy, by using clinical, histopathologic, or newer diagnostic approaches and to determine the long-term effect (20-50 years) of the pouch-reservoir procedures on malignancy potential. This session reviewed various aspects of the prevention and early detection of malignancy in inflammatory bowel disease (IBD). Barbara Kirschner, M.D., University of Chicago Children's Hospital, Chicago, Illinois, organized and moderated this session. Discussants were Bernard Levin, M.D., from the University of Texas, M. D. Anderson Cancer Center, Houston, Texas; Robert Riddell, M.D., from McMaster University Medical School, Hamilton, Ontario, Canada; James Markowitz, M.D., from North Shore University Hospital, Manhasset, New York; and Neil Leleiko, M.D., from Mount Sinai Medical Center, New York, New York. Gastrointestinal Neoplasia in Ulcerative Colitis Dr. Levin discussed the difficulty in assessing premalignant lesions and the magnitude of the risk of neoplasia. He emphasized that different methods have been used to compile and analyze data (e.g., population-based vs. hospital-based studies). For example, Lennard-Jones et al. (5) reported a 13- to 19-fold increase in relative risk when hospital-based studies are used. This is compared with a much lower risk (twofold) found in populationbased studies from Denmark or Sweden. Thus reports of cancer frequency may be affected not only by the extent, severity, and duration of disease, and age of onset, but also by referral bias. Early colectomy appears to diminish the cancer risk (6). In general, most modern series reported a cumulative risk of cancer of 11-12% at 25 years. Evidence that the extent of inflammation has a direct bearing on the overall risk of cancer is based on the observation that patients with extensive disease, particularly proximal to the hepatic flexure, have a significantly greater risk than do individuals with proctitis (7). The debate continues as to whether primary sclerosing cholangitis increases cancer risk. Whereas one United States study noted an increased risk (8), Broome et al. (9), by using patients in a defined geographic area, showed no increased risk. Current recommendations are that patients with UC under consideration for liver transplantation should undergo preoperative colonoscopy to exclude dysplasia. Understanding the mechanisms of developing neoplasia may provide earlier and more accurate tools for detection. Mutations of p53, or loss of heterozygosity, appear to occur earlier in IBD-associated cancer than in sporadic cancers. However, they are not universally present in dysplasia or cancer. K-ras mutations occur later and with equal frequency in UC-associated and sporadic cancers. Recent reports by Iskowitz et al. (10) describe overexpression of sialosyl-Tn antigen preceding dysplasia in UC; this may prove to be a useful tool as experience accumulates. Cancer surveillance is a continuous process of clinical evaluation and investigation. Lesions may be subtle, so the entire colon should be examined and jumbo forceps used with special attention to plaques, strictures, and villous areas. Even with obtaining three biopsies every 10 cm, <1% of the mucosal surface is evaluated. Decision analysis in individuals with LGD has changed. The evidence now suggests that LGD should lead to colectomy, much as HGD has in the past. Indeterminate dysplasia should prompt repeated colonoscopy at short intervals (6 months); negative colonoscopy after indeterminate findings should lead to frequent (1- to 2-year) follow-up. It should be remembered that only 78% of patients have dysplasia adjacent to a cancer, and 74% have dysplasia distant to a cancer, emphasizing that dysplasia is not universally present in patients with colon cancer (11). Although it is not foolproof, dysplasia surveillance makes sense. A recent meta-analysis by Sherman and Griffiths (12) indicated that surveillance colonoscopy does reduce both the frequency and stage of colitis-associated colon cancer. The aim of surveillance is not to detect cancer but to try to detect or prevent precancer and remove the risk. The goal of surveillance is to save lives, not to save colons. Teenagers and young patients going to college are at higher risk for a breakdown in surveillance approaches. These patients are often unlikely to accept their increased cancer risk, and in general, teenagers have infrequent health check-ups when they are not ill. As with any individual, if surveillance is not possible because of anatomy, numerous polyps, or poor access to medical facilities, a surgical solution to cancer prevention should be advocated, recognizing that this also requires patient understanding of the risks and benefits. The issue of when surveillance should start for patients diagnosed during infancy is not answered by evidence-based studies. Most agree that a prospective program of surveillance or colectomy or both should be initiated in a pediatric patient with long-standing pancolitis, although there is not consensus on when the benefits of these approaches are first appreciated. Reliability, Validity and Problems of Surveillance in Identifying At-Risk Patents with Ulcerative Colitis Cancers in colitis are different from the usual carcinomas; they are often flat and plaque-like. Dr. Riddell emphasized that dysplasia is an unequivocally neoplastic change, which can give rise to invasive carcinomas. If LGD is found, resection is the only certain means of excluding an underlying invasive adenocarcinoma. The terms “mild dysplasia” or “moderate dysplasia” should no longer be used. Among the major problems associated with surveillance colonoscopy is sampling error, because dysplasia may be found in random biopsies from visually normal mucosa. He agreed with Dr. Levin's recommendation of 32 evenly spaced biopsies but cautioned that even if an area of dysplasia is found, it is not clear that it could be found again on repeated colonoscopy, so that such an undertaking is potentially not effective or efficient. Interobserver variability is the second problem he commented on (13–16). For a given reference specimen with LGD, 25% of pathologists will report the diagnosis as indeterminate, and 25% will report HGD. Some simplification can be achieved by recognizing the end point as dysplasia, no matter what the grade. Further, to support the case for early colectomy, Dr. Riddell stated that the long-term risk of developing cancer was the same for patients whose biopsies were indefinite for dysplasia and for those with LGD. With 40 years of follow-up, 60% of these patients develop either HGD or cancer. He stated that most pediatric patients will come to colectomy and that it may be an issue of timing rather than whether they will need colectomy. In support of the value of surveillance, Dr. Riddell agreed with Dr. Levin that the Scandinavian experience shows that cancers can be detected at an earlier stage (17–20). More cancers classified as Dukes A and B are found in patients in surveillance programs compared with higher grade tumors and higher mortality in individuals not in surveillance programs. Similar to the point raised by Dr. Levin, he stated that gastroenterologists should think of surveillance as dysplasia surveillance rather than cancer surveillance. Increasing the accuracy of detecting precancerous mucosa may result from the use of newer diagnostic tools. Sialosyl-Tn antigen is detected with increased frequency in patients with dysplasia but does not yet have sufficient sensitivity or specificity to be of clinical value (10). Assessment of oncogenes by using washings or brushings may be useful for detecting tumor-suppressor genes or mutator phenotypes. Several immunohistochemical markers of proliferation are under study. In particular, p53 stain can be helpful in distinguishing reactive changes from LGD, because p53 is present in a large proportion of patients with dysplasia. Flow cytometry to detect aneuploidy holds promise, as it may be present before unequivocal dysplasia develops. It may be particularly helpful in evaluating patients who are indefinite for dysplasia. Modalities that make difficult-to-detect endoscopic lesions more visible could be valuable in permitting endoscopically targeted biopsies, which give the highest yield. Newer techniques such as detection with lasers, magnification endoscopy, and dye-spraying techniques may detect abnormal mucosa more effectively than currently practice, but have not yet been critically evaluated. Dr. Riddell's recommendations agree with those expressed by Dr. Levin. When biopsy findings are negative for dysplasia, annual or biannual surveillance colonoscopy is sufficient; patients whose biopsies are indefinite for dysplasia should undergo repeated colonoscopy, whereas unequivocal dysplasia should be an indication for resection. He quoted a recent study (21) in which the risk of invasive cancer was 40% in patients with dysplasia-associated lesions or masses (DALM), 32% in those with HGD, 20% in those with LGD, and 10% in those indefinite for dysplasia undergoing repeated colonoscopy. Eleven (2%) of 595 patients had cancer with no detectable dysplasia. A final point relates to the issue of dysplasia in ileoanal anastomotic pouches. Aneuploidy, LGD, and cancer have all been seen in a pouch. Many people regard pouchitis as a recurrence of IBD in a pouch that has been colonized. Thus the question remains whether by constructing a pouch, the dysplasia/cancer sequence has simply been pushed back another decade or two. Patients having 1-2 cm of rectal mucosa at the rim may also be at subsequent cancer risk. Cancer Risk and Endoscopic Cancer Surveillance Dr. Markowitz presented the results of prospective studies comparing aneuploidy and dysplasia with the risk of cancer in a group of pediatric patients diagnosed with colitis (UC and CD) younger than 15 years (22). His study population consisted of 35 subjects with childhood-onset colitis (18 UC, 17 CD) of >8 years' duration. Aneuploidy was detected in seven (20%) patients, equally divided between UC and CD. Dysplasia was found in two of seven on the first colonoscopy but only one of two on repeated colonoscopy, demonstrating the difficulties cited previously by Drs. Levin and Riddell. Resection was performed in five of seven; both patients with dysplasia seen on endoscopy had dysplasia at surgery. In addition, another patient was discovered to have cancer associated with aneuploid mucosa but not dysplasia. Therefore this group provides evidence that aneuploid assessment may be helpful in identifying patients at risk for neoplastic change. In another study (23), Markowitz et al. evaluated an immunohistochemical stain for p53 in this population. This study consisted of 34 patients: 10 with UC, six with ulcerative proctitis, and 18 with Crohn's colitis. Their results showed that if either flow cytometry or p53 was normal, no dysplasia or cancer was found at surgery. When both aneuploidy and p53 were positive (five subjects), one patient had dysplasia, one patient had cancer, and three had neither dysplasia nor cancer. He suggested that the simultaneous expression of abnormal p53 and aneuploidy may represent a new indication for surgery in pediatric patients with long-standing colitis. Dr. Markowitz also discussed the need for identifying methods other than those dependent on patient follow-up. He cited data (24) in which five of 22 patients had no recall of the discussion regarding the need for surveillance colonoscopy. This led to the conclusion that physicians must take an active role in assuring that patients are enrolled in a surveillance program. Risk of Developing a Malignancy as a Result of Immunosuppressive Therapy The challenge of the final speaker was to determine from reviewing the literature whether the use of immunosuppressive drugs increases the risk of malignancy in patients with IBD. Unfortunately, a paucity of evidencebased literature exists at present. Dr. Leleiko noted that reports generally categorize cancers associated with immunosuppression into carcinoma and non-Hodgkin lymphoma (NHL). In the case of NHL, based on anecdotal reports, the approximate risk was calculated by Dr. Leleiko to be one case per 500 patient-years with 6- mercaptopurine (6-MP). He expressed the opinion that this gives cause for concern if the child is clinically well, has a resectable lesion, or could be managed effectively without this drug or similar agents. He advised trying to set an end point, such as growth rate or fistula closure, to limit the duration of treatment with these drugs. However, in a study addressing this point (25), among patients with extensive chronic IBD, there was no difference in NHL or cancer frequency between 86 who had received azathioprine and 180 matched patients who had never received it. Thus it is not clear whether development of NHL reflects the characteristics of autoimmune chronic inflammatory disease or whether NHL is increased by immunosuppressive drug therapy. References 1.Devroede GJ, Taylor WF, Sauer WG, Jackman RJ, Stickler GB. Cancer risk and life expectancy of children with ulcerative colitis. N Engl J Med 1971;285:17-21. 2.Langholz E, Munkholm P, Davidsen M, Binder V. Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology 1992;103:1444-51. 3.Ekbom A, Helmick C, Zack M, Adami H-O. Ulcerative colitis and colorectal cancer: a population-based study. N Engl J Med 1990; 323:1228-33. 4.Ekbom A, Helmick C, Zack M, Adami H-O. Increased risk of large-bowel cancer in Crohn's disease with colonic involvement. Lancet 1990;336:357-9. 5.Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 1990;31:800-6. 6.Hendriksen C, Kreiner S, Binder V. Long-term prognosis in ulcerative colitis: based on results from a regional patient group from the county of Copenhagen. Gut 1987;26:158-63. 7.Maratka Z, Nedbal J, Kocianova J, Havelka J, Kudrmann J, Hendl J. Incidence of colorectal cancer in proctocolitis; a retrospective study of 959 cases over 40 years. Gut 1985;26:43-9. 8.D'Haens GR, Lashner BA, Hanauer SB. Pericholangitis and sclerosing cholangitis are risk factors for dysplasia and cancer in ulcerative colitis. Am J Gastroenterol 1993;88:1174-8. 9.Broome U, Lindberg O, Lofberg R. Primary sclerosing cholangitis in ulcerative colitis: a risk factor for the development of dysplasia and DNA-aneuploidy? Gastroenterology 1992;102: 1877-80. 10.Itzkowitz SH, Young E, Dubois D, et al. Sialosyl-Tn antigen is prevalent and precedes dysplasia in ulcerative colitis: a retrospective case-control study. Gastroenterology 1996;110:694-704. 11.Isbell G, Levin B. Ulcerative colitis and colon cancer. Gastroenterol Clin North Am 1988;17:773-93. 12.Griffiths AM, Sherman PM. Colonoscopic surveillance for cancer in ulcerative colitis: a critical review. J Pediatr Gastroenterol Nutr 1997;24:202-10. 13.Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel-disease: standard classification with provisional clinical applications. Hum Pathol 1983;14:931-68. 14.Melville DM, Jass JR, Morson BC, et al. Observer study on the grading of dysplasia in ulcerative colitis: comparison with clinical outcome. Hum Pathol 1989;20:1008-14. 15.Dixon MF, Brown LJ, Gilmour HM, et al. Observer variations in the assessment of dysplasia in ulcerative colitis. Histopathology 1988;13:385-97. 16.Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994;107:934-44. 17.Jonsson B, Ahsgren L, Andersson LO, Stenling R, Rutegard J. Colorectal cancer surveillance in patients with ulcerative colitis. Br J Surg 1994;81:689-91. 18.Leidenius M, Kellokumpu I, Husa A, Riihela M, Sipponen P. Dysplasia and carcinoma in longstanding ulcerative colitis: an endoscopic and histological surveillance programme. Gut 1991;32: 1521-5. 19.Lofberg R, Brostrom O, Karlen P, Tribukait B, Ost A. Colonoscopic surveillance in long-standing total ulcerative colitis-a 15-year follow-up study. Gastroenterology 1990;9: 1021-31. 20.Lynch DA, Lobo AJ, Sobala GM, Dixon MF, Axon AT. Failure of colonoscopic surveillance in ulcerative colitis. Gut 1993;34:1075-80. 21.Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994;343:71-4. 22.Markowitz J, McKinley M, Kahn E, et al. Endoscopic screening for dysplasia and mucosal aneuploidy in adolescents and young adults with childhood onset colitis. Am J Gastroenterol 1997;92: 2001-6. 23.Kahn E, Markowitz J, Malik S, Boss E, Stiel L, Daum F, McKinley M. Relationship between DNA ploidy states and immunohistochemical identification of p53, bcl-2 and PCNA in colorectal biopsies of patients with colitis. Gastroenterology 1996; 110:A537. 24.Markowitz J, Shaffiroff M, Cellini C, Grancher K, Aiges H, Daum F. The need for medical care and endoscopic surveillance: a survey in young adults with childhood onset ulcerative colitis. Am J Gastroenterol 1995;90:1644A. 25.Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994;343: 1249-52. Session 5. Hepatobiliary Complications of Inflammatory Bowel Disease: Overview of the Issues William F. Balistreri Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio, U.S.A. Overview of the Issues A wide variety of hepatobiliary lesions have been reported to occur in ≤10% of patients with inflammatory bowel disease (IBD; 1-3). The clinical significance of these complications is broad; some are inconsequential, others are potentially fatal. Primary sclerosing cholangitis (PSC), the most common form of chronic liver disease recognized in patients with IBD, is a chronic diffuse fibrosing inflammation that affects the intra- and extrahepatic bile ducts. Progressive obliteration of the bile duct lumen may occur; therefore there is the potential for progression to cirrhosis. With the advent of reliable cholangiographic techniques, it has been easier to document the presence and high prevalence of large-duct PSC. PSC is especially associated with UC: as many as 80% of adult patients with PSC may have UC (4). The pathogenesis is unknown. Therapy is empiric and aimed at controlling inflammation, preventing scarring, and addressing the clinical manifestations (1,5) (Table 1). Multiple questions regarding these complications, their pathogenesis, recognition, and potential therapy must be addressed. What are the diagnostic criteria for PSC? Is PSC in the pediatric age population analogous to PSC in adults? Are there unique pediatric aspects? What is the etiopathogenesis? How do we treat affected patients? The purpose of this session was to discuss these issues. William F. Balistreri, M.D., from Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio, organized and moderated this session. Discussants were Jeffrey S. Hyams, M.D., from Connecticut Children's Hospital and the University of Connecticut, Hartford, Connecticut; Steven Lichtman, M.D., from the University of North Carolina, Chapel Hill, North Carolina; Jean Perrault, M.D., from the Mayo Clinic, Rochester, Minnesota; and Kenneth Cox, M.D., from the Lucille Packard Children's Hospital and Stanford University, Palo Alto, California. Table 1. Goals of therapeutic intervention in patients with PSC Open in new tab Table 1. Goals of therapeutic intervention in patients with PSC Open in new tab Incidence/Prevalence Dr. Jeffrey S. Hyams discussed the incidence of hepatobiliary complications of IBD, emphasizing that although it is important to recognize that clinical liver disease is unusual in IBD, abnormalities of serum aminotransferases (ALT) are relatively common (Table 2). Hepatobiliary disease can occur before the clinical onset of IBD or many years after diagnosis. However, the specific incidence or prevalence remains to be defined and depends, in part, on disease identification; this will vary with the population being studied (community based vs. tertiary center based). At present, hepatobiliary disease can be identified in several ways, including finding abnormal liver tests, suggestive symptoms, abnormal ultrasonography, or hepatic biopsy. If the assumption is made that PSC can be present in small intrahepatic ducts only, in extrahepatic ducts only, or in both, then cholangiography and liver biopsy are required as part of the evaluation to exclude this disorder. Dr. Hyams emphasized the diagnostic difficulty by citing the Mayo Clinic series of 400 adult patients; 12% had normal ALT and alkaline phosphatase (AP) values and the diagnosis of PSC was made by endoscopic retrograde cholangiopancreatography (ERCP) during workup of symptoms such as abdominal pain or pruritus (6). Truly to define the incidence and prevalence of liver disease in patients with IBD would therefore require prospective (serial) studies of consecutive patients with IBD by using cholangiograms and wedge biopsies! It has been especially difficult to gain perspective on the incidence in the pediatric population because ERCPs are infrequently performed, and normal values are not defined; in addition, few clinicians have experience with this technique. Thus there are few pediatric studies (2,7–12). Table 2. Relative frequency of hepatobiliary manifestations of IBD Open in new tab Table 2. Relative frequency of hepatobiliary manifestations of IBD Open in new tab Dr. Hyams cited his report (8), in which 555 patients with IBD from the Hartford/Northshore combined experience were screened for evidence of liver disease; the criterion for inclusion was ALT >80 U/L. Overall, 14% of patients were noted to have an abnormal ALT during the course of their illness; three patterns were described: Persistent increase of ALT levels (≥6 months) occurred in 14 patients. All were found to have significant liver disease, including PSC in eight patients with UC (3.5% of all patients with UC) and in two (0.6%) patients with CD, similar to adult series. Chronic hepatitis was found in 0.9% of all patients with CD and in 0.4% of all patients with UC; an abnormal ALT was noted in the latter group before the onset of IBD. In long-term (1- to 13-year) followup of 10 patients with PSC, one required liver transplantation. Of four patients with chronic hepatitis, two had symptomatic liver disease. A single episode of ALT increase was noted incidentally during the course of IBD in 49 patients (33 of 318 with CD and 16 of 237 with UC); 10 of the 49 increased levels were noted at the time of diagnosis of IBD and were then normal in follow-up (1 year). The potential causes included medications, disease flare, parenteral nutrition, massive weight gain, transfusion, or viral illness. Intermittent ALT increase with eventual normalization was found in 12 patients; the origin was similar to that noted in group 2. Dr. Hyams concluded that an abnormal serum ALT is commonly found during the course of IBD; this is usually transient and appears to be related to medications or disease activity. PSC develops in -3.5% of patients with UC and <1% of patients with CD. Chronic hepatitis develops in <1% of children with IBD. Therefore Dr. Hyams' personal practice is routinely to measure liver enzymes at least twice a year. Unless other symptoms are present, he believes that observation of the patient with an increased ALT is appropriate. Persistent increase of ALT (>6 months) should be investigated, as the likelihood of serious liver disease is high. Pathogenesis of PSC Dr. Steven N. Lichtman discussed potential etiologies, emphasizing that the precise mechanism of how PSC lesions develop in IBD is unknown and that cholangiographic changes resembling PSC can occur with a wide variety of diseases (celiac disease, sarcoidosis, chemical injury, etc.). Theories of pathogenesis must explain the apparent link between PSC and intestinal inflammation (e.g., increased mucosal permeability, overgrowth of anaerobic luminal bacteria). It is likely that the pathogenesis is multifactorial-a combination of bacterial contamination and an enhanced susceptibility to infection (genetic or acquired). Theories of pathogenesis include: Bacterial or toxin-induced hepatobiliary disease. It is hypothesized that absorption of a toxin (e.g., lithocholic acid) or viable bacteria from the inflamed colon leads to a low-grade bacterial cholangitis. The association between PSC and chronic pouchitis in IBD might be further examined in this regard (13). However, it was emphasized that absorption of toxins or bacteria from the colon may not be relevant because 5-30% of patients with PSC do not have UC, or any detectable bowel lesion, and that some cases of PSC occur before the onset of colitis. The presence or intensity of PSC does not correlate with the colonic disease severity, and it may even develop after colectomy, seemingly negating a role for the gut as the site of generation of an hepatotoxic factor. Viral pathogenesis. A virus could theoretically infect and alter cholangiocytes, which then become the target of an autoimmune attack (3). Although attractive as an acute initiating insult to the biliary tree, there is no direct evidence of viral infection or injury, nor has a consistent candidate been isolated. Genetic predisposition. It has been noted that there is an increased association of PSC with HLA-B8 and HLA-DR3. In patients with UC who are HLA-B8/ DR3 positive, there is a 10-fold increased chance of PSC. How this genetic predisposition relates to disease is not clear. In addition, HLA-DR4 positivity has been an indicator of a more rapidly progressive disease (14). Immunologic component. This is suggested by the high coincidence of PSC with other autoimmune diseases and frequent antineutrophil cytoplasmic antibodies with perinuclear (p-ANCA) positivity (15,16). Dr. Lichtman discussed several animal models that were used to explore the mechanism of hepatobiliary inflammation associated with intestinal injury. Specifically, he developed an animal model for chronic hepatobiliary injury by inducing lesions reminiscent of PSC (portal inflammation and bile duct proliferation) in genetically susceptible rats with experimental small bowel bacterial overgrowth (17–19). Dr. Lichtman's hypothesis is that bacterial polymers are absorbed from the intestinal lumen and activate Kupffer cells, leading to the release of proinflammatory cytokines, which mediate the hepatobiliary lesion. The target could be bile duct epithelial cells. There may be a genetic predisposition leading to increased absorption of bacterial polymer, increased sensitivity to bacterial polymers, or poorly functioning host degradative enzymes. An alternative hypothesis is that reactive xenobiotic metabolites (exogenous agents, chemicals, smoking), which are conjugated before excretion into bile, may induce disease. Perhaps inherited differences in host drug metabolism account for the genetic influences observed [e.g., bacteria in the colon deconjugate and release the reactive metabolite, which injures the colonic epithelium or biliary epithelia or both (20)]. Clinical Recognition Dr. Jean Perrault discussed the clinical manifestations and screening for liver disease in patients with IBD. Although most hepatobiliary diseases accompanying IBD seen in adults have also been described in children, they are less severe in children or may respond to therapy directed at IBD itself (9,21). He reemphasized the need initially to differentiate other potential hepatobiliary diseases that can occur in patients with IBD, including viral hepatitis (rare), and drug-induced lesions from those directly related to IBD. He discussed the specific difficulty in separating PSC from chronic hepatitis. In patients with chronic hepatitis, colitis occurs more commonly in those who are smooth muscle antibody positive and is not seen in liver/kidney microsomal antibody positive patients (22,23). Chronic hepatitis associated with IBD in adults is usually less responsive to medical therapy (corticosteroids) and is more likely to progress to cirrhosis, underscoring the overlap between autoimmune hepatitis and PSC (24). The diagnosis of PSC is dependent on a combined assessment of liver tests, cholangiography (endoscopic or transhepatic), and liver histology. The characteristic features found in liver biopsy specimens from patients with PSC are ductal lesions, in sequential order or as concomitant lesions. These include bile duct proliferation, periductal fibrosis, periductal inflammation (onionskin lesions), ductal obliteration, and loss of bile ducts along with portal edema and fibrosis, portal and periportal hepatitis, and parenchymal changes. Ludwig (25) proposed four stages based on biopsy/autopsy specimens from 43 patients with PSC (either with or without UC) and from 19 patients with UC without PSC (Table 3). Pathognomonic histologic changes occur in the early stages: fibrous-obliterative cholangitis, leading to replacement of duct segments by solid cords of connective tissue and to complete loss of interlobular and adjacent septal bile ducts with time. With progression, there is an increase in portal fibrosis, a decrease in the number of interlobular bile ducts, bridging, and progression to biliary cirrhosis. Cholangiographically, both the intra- and extrahepatic bile ducts show diffuse beading and irregular narrowing and stricture of the hepatic and common bile duct due to fibrosing inflammation with or without involvement of intrahepatic ducts (segmental stenosis); these lesions are widespread, diffuse, and multifocal (3,26). Occasionally only one or the other is affected, although it is unusual to see change in the intrahepatic bile ducts only. The pancreatic duct and the gallbladder may be affected. Table 3. Progression of histologic changes in PSC Open in new tab Table 3. Progression of histologic changes in PSC Open in new tab The diagnostic approach to children with IBD and suspected PSC has been infrequently studied. The clinical presentation and outcome of 32 children with PSC were reviewed by Wilschanski et al. (12). The majority were diagnosed in their second decade (median age, 13 years; none in the neonatal period); 17 of 32 had IBD (14 had UC and three, CD). Eight patients had chronic liver disease before the clinical onset of IBD. At presentation, eight of 32 patients were jaundiced; 15 of 32 had normal AP; and nine had features of autoimmune hepatitis. On cholangiography, intrahepatic disease predominated. There was an increased incidence of HLA B8 and DR2; ANCA was positive in 10 of 24 patients tested. In Dr. Perrault's experience, 30% of patients with PSC had a normal AP at diagnosis; however, all had abnormal γ-glutamyl transferase (GGT) levels. Dr. Perrault emphasized that prognostic features for pediatric patients must be defined. Management Dr. Kenneth Cox discussed the management of hepatobiliary complications of IBD. Various medical approaches to the treatment of the underlying hepatobiliary disease in adults with PSC primarily focused on the use of cupruretic, antifibrogenic, and immunosuppressive agents. There are no published controlled trials of any totally effective form of medical therapy in PSC. Administration of ursodeoxycholic acid (UDCA) has been associated with some improvement in clinical manifestations of PSC in a few studies, but not in all (3,5,27–29). Lindor et al. (30) reported a large placebocontrolled study of long duration, which indicated that UDCA significantly improved the results of biochemical tests in adults with PSC. However, there are not sufficient data to indicate whether this drug offers long-term benefit on clinically important end points (e.g., the need for transplantation) and if so, at what dose and by what mechanism (31). Complications of bacterial cholangitis and strictures of the biliary tree are common in PSC and are treatable. Because of high biliary concentrations and broad bacterial coverage, ciprofloxacin has been effective therapy for bacterial cholangitis (3). No controlled trials evaluated the efficacy of prophylactic antibiotic therapy to reduce the frequency of bacterial cholangitis. Dr. Cox presented data regarding his use of oral vancomycin in three children with PSC; liver enzymes normalized during therapy. This might support the concept of an important role for intraluminal bacteria in the pathogenesis of PSC. However, long-term benefit in larger numbers of patients must be documented. Interventional or surgical therapy also was used. Balloon dilatation and long-term stenting by a transhepatic or endoscopic retrograde approach may alleviate dominant strictures and assist in treatment of recent-onset cholangitis; however, this has not been effective in cases of long-standing recurrent bacterial cholangitis (32,33). Choledochoduodenostomy or choledochojejunostomy may be palliative in the treatment of obstruction and bacterial cholangitis in patients for whom balloon dilatation and stenting failed (3). However, there are no data for children. Proctocolectomy does not have a beneficial effect on PSC (34). Liver transplantation has been effective treatment for end-stage liver disease of PSC, with a >85% 5-year survival (3,35–37). In patients with PSC, there appears to be an increased risk of rejection, of biliary strictures, and of recurrence (35,37). Cholelithiasis, which is common in patients with CD, and after ileocolectomy, should be managed in a manner similar to that used for patients with gallstones without associated IBD. Conclusion This session provided an update of our state of knowledge and pointed out gaps in our understanding of hepatobiliary lesions in pediatric patients with IBD. These challenges cited should stimulate research in this area. References 1.Balistreri WF, Bove KE. Sclerosing cholangitis. In: Suchy FJ, ed. Liver Disease in Children. Boston: Mosby, 1994:622-37. 2.Hyams JS. Extraintestinal manifestations of inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr 1994;19:7-21. 3.LaRusso NF. Hepatobiliary disease in inflammatory bowel disease. Gastroenterol Clin North Am 1995;24:647-69. 4.Wiesner RH. Advances in primary sclerosing cholangitis. In: zum Biischenfelde K-HM, Hoofnagle JP, Manns M, eds. Immunology and liver. Boston: Kluwer Academic Publishers, 1993:295-306. 5.Mitchell SA, Chapman RWG. Review article: the management of primary sclerosing cholangitis. Aliment Pharmacol Ther 1997;11: 33-43. 6.Balasubramaniam K, Wiesner RH, LaRusso RH, LaRusso NF. Primary sclerosing cholangitis with normal serum alkaline phosphatase. Gastroenterology 1988;95:1395-8. 7.Debray D, Pariente D, Urvoas E, Hadchouel M, Bernard O. Sclerosing cholangitis in children. J Pediatr 1994; 124:49-56. 8.Hyams J, Markowitz J, Treem W, et al. Characterization of hepatic abnormalities in children with inflammatory bowel disease. Inflammatory Bowel Diseases 1995;1:27-33. 9.Nemeth A, Ejderhamn J, Glaumann H, Strandvik B. Liver damage in juvenile inflammatory bowel disease. Liver 1990; 10:239-48. 10.Ong JC, O'Loughlin EV, Kamath KR, Dorney SF, de Silva M, Gaskin KJ. Sclerosing cholangitis in children with inflammatory bowel disease. Aust NZ J Med 1994;24:149-53. 11.Toghill PJ, Benton KPE, Smith PG. Chronic liver disease associated with childhood ulcerative colitis. Postgrad Med J 1974;50:9-15. 12.Wilschanski M, Chait P, Wade JA, et al. Primary sclerosing cholangitis in 32 children: clinical, laboratory and radiographic features with survival analysis. Hepatology 1995;22:1415-22. 13.Penna C, Dozois R, Tremaine W, et al. Pouchitis after ileal pouch: anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut 1996;38:234-9. 14.Mehal WZ, Lo YMD, Wordsworth BP, et al. HLA DR4 Is a marker for rapid disease progression in primary sclerosing cholangitis. Gastroenterology 1994;106:160-7. 15.Lo SK, Chapman WG, Cheeseman P, et al. Antineutrophil antibody: a test for autoimmune primary sclerosing cholangitis in childhood? Gut 1993;34:199-202. 16.Vidrich A, Targan SR. Antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis and ulcerative colitis. In: zum Biischenfelde K-HM, Hoofnagle JP, Manns M, eds. Immunology and liver. Boston: Kluwer Academic Publishers, 1993:324-30. 17.Lichtman SN, Keku J, Clark RL, Schwab JH, Sartor RB. Biliary tract disease in rats with experimental bacterial overgrowth. Hepatology 1991;13:766-72. 18.Lichtman SN, Keku J, Schwab JH, Sartor RB. Metronidazole and tetracycline prevent hepatic injury associated with small bowel bacterial overgrowth in rats. Gastroenterology 1991;100:513-9. 19.Lichtman SN, Sartor RB, Keku J, Schwab JH. Hepatic inflammation in rats with experimental small bowel bacterial overgrowth. Gastroenterology 1991;98:414-23. 20.Crotty B. Ulcerative colitis and xenobiotic metabolism. Lancet 1994;343:35-8. 21.Kane W, Miller K, Sharp HL. Inflammatory bowel disease presenting as liver disease during childhood. J Pediatr 1980;97: 775-8. 22.Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology 1997;25:541-7. 23.Maggiore G, Veber F, Bernard O, et al. Autoimmune hepatitis associated with anti-actin antibodies in children and adolescents. J Pediatr Gastroenterol Nutr 1993;17:376-81. 24.Czaja AJ. The variant forms of autoimmune hepatitis. Ann Intern Med 1996;125:588-98. 25.Ludwig J. Surgical pathology of the syndrome of primary sclerosing cholangitis. Am J Surg Pathol 1989;13:43-9. 26.MacCarty RL, LaRusso NF, Wiesner RH, Ludwig J. Primary sclerosing cholangitis: cholangiographic appearances. Radiology 1983; 149:39-44. 27.Beuers U, Spengler U, Kruis W, et al. Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial. Hepatology 1992;16:707-14. 28.O'Brien CB, Senior JR, Arora-Mirchandani R, Batta AK, Salen G. Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30 month pilot study. Hepatology 1991;16:838-47. 29.Van Thiel DH, Wright HI, Gaveler JS. Ursodeoxycholic acid (UDCA) therapy for primary sclerosing cholangitis (PSC): preliminary report of a randomized controlled trial. Hepatology 1992; 16: 71. 30.Lindor KD. Ursodiol for primary sclerosing cholangitis. N Engl J Med 1997;336:691-5. 31.Balistreri WF. Bile acid therapy in pediatric hepatobiliary disease: the role of ursodeoxycholic acid. J Pediatr Gastroenterol Nutr 1997;24:573-89. 32.Bender CE, Wiesner RH, LeRoy AJ, et al. Clinical improvement following percutaneous balloon dilatation of dominant bile duct structures in primary sclerosing cholangitis. Gastroenterology 1992;102:A780. 33.May GR, Bender CE, LaRusso NF, Wiesner RH. Nonoperauve dilatation of dominant strictures in primary sclerosing cholangitis. Am J Radiol 1985;145:1061-4. 34.Cangemi JR, Wiesner RH, Beaver SJ, et al. Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology 1989;96:790-4. 35.Harrison J, McMaster P. The role of orthotopic liver transplantation in the management of sclerosing cholangitis. Hepatology 1994;20:14S-9S. 36.Narumi S, Roberts JP, Emond JC, Lake J, Ascher NL. Liver transplantation for sclerosing cholangitis. Hepatology 1995;22:451-7. 37.Wiesner RH, Porayko MK, Dickson ER, et al. Selection and timing of liver transplantation in primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 1992;16:1290-9. Session 6. Management of Severe Colitis/Ileocolitis Richard J. Grand New England Medical Center, Boston, Massachusetts, U.S.A. Introduction This panel was devoted to an assessment of the challenges and therapy of severe, fulminant colitis and toxic megacolon in the context of newly available medical therapy and advances in surgical treatment. Richard J. Grand, M.D., from New England Medical Center, organized and moderated this session. Discussants were Steven L. Werlin, M.D., from the Medical College of Wisconsin, Milwaukee, Wisconsin; Frederic Daum, M.D., from North Shore University Hospital, Manhasset, New York; William R. Treem, M.D., from Duke University Medical Center, Durham, North Carolina; William J. Sandborn, M.D., from Mayo Clinic, Rochester, Minnesota; and Daniel P. Doody, M.D., from Massachusetts General Hospital, Boston, Massachusetts. Dr. Werlin discussed the presentation of severe or fulminant colitis. This can be the initial feature of disease or can occur in the setting of a relapse of inflammatory bowel disease in -10% of affected children and adolescents. The findings of active grossly bloody diarrhea are often accompanied by fever, abdominal tenderness, and abnormal laboratory tests. The presence of these findings with marked colonic distention is known as toxic megacolon. Severe colitis and toxic megacolon can occur in patients with ulcerative colitis or Crohn's disease. Dr. Werlin pointed out that to standardize terminology and test the effectiveness of cortisone in ulcerative colitis, Truelove and Witts (1) defined severe colitis in adults by using the criteria shown in Table 1. Many subsequent studies of severe or fulminant ulcerative colitis have used these criteria. Indeed, Travis et al. (2) recently used these criteria to enter patients into an interesting outcome study. Patients with severe ulcerative colitis who fulfilled these criteria were followed up carefully by using additional clinical and laboratory measures. On day 3 of illness, if the Creactive protein levels were >45 mg/L or patients were having more than eight stools per day, 85% failed medical therapy and were treated surgically. On day 7, of those who had more than three stools per day with visible blood, 40% failed medical management. Of those adults achieving a partial remission, 40% required surgery within 4 months of the onset of illness. In 1977, recognizing that the Truelove and Witts criteria were not ideal for use in children, Werlin and Grand (3) modified these criteria for use in children (Table 1). To be classified as having severe colitis, patients were required to fulfill four of the first five criteria or criterion 6 (toxic megacolon) alone. In this study of 19 children, the success rate for medical treatment was 31%. In the group of responders, five (56%) of nine required total proctocolectomy and ileostomy by 2 years after remission. Table 1. Severe colitis Open in new tab Table 1. Severe colitis Open in new tab Severe Colitis in Children As discussed by Dr. Daum, in the 1990s, life-threatening hemorrhage remains a common feature of severe ulcerative colitis in childhood and adolescence; toxic megacolon has become a rare occurrence. Although rapid diagnosis and recognition of Clostridium difficile-related disease, as well as broader spectrum antibiotics, may explain these findings, the decreased use of opiates and antispasmodics (as well as the avoidance of invasive tests such as barium enema or colonoscopy), known for years to precipitate toxic megacolon, may explain the lowered prevalence of this complication. Except for a recent publication by Gold et al, (4) in which there was a 91% response to prolonged, in-hospital medical therapy, it is apparent from the literature that most pediatric gastroenterologists believe that they cannot rely on corticosteroid therapy to control severe ulcerative colitis in children. Therefore there has been a significant effort to evaluate immunosuppressive medications (particularly cyclosporine) as adjunctive therapy in an effort to achieve remission with medical treatment (5). The challenge here is the potential risks and benefits of potent immunosuppressives just to avoid surgery. Dr. Daum pointed out that the goal of therapy in severe colitis is to treat the patient, not to save the colon. Use of Cyclosporine a for Severe/Fulminant Colitis The role of cyclosporine in the treatment of severe colitis was discussed by Dr. Treem. There are to date 33 children and adolescents reported whose severe colitis has been treated with cyclosporine (6–11). In most protocols, cyclosporine has been added to high-dose steroids when disease activity is refractory to steroids and parenteral nutrition. The doses of cyclosporine used have varied greatly, but the outcomes have been similar. In young patients with both ulcerative and Crohn's colitis, 75% achieved remission. However, over a 3- to 24-month follow-up period, only eight (32%) of 25 with ulcerative colitis were able to maintain remission, and the remainder underwent surgery. This is approximately the same rate as reported by Werlin and Grand before the cyclosporine era. Of 12 children reported with Crohn's colitis, only four (33%) maintained sustained remission for longer than 6 months when weaning off cyclosporine, whereas eight went on to surgical treatment. Weaning patients from cyclosporine to other immunosuppressive medications did not necessarily protect them from the need for surgery (8). Although the side effects of cyclosporine therapy have been mild and manageable (7,8), concerns about the risks lessen enthusiasm for long-term use, or treatment of patients with long-standing disease. In the acute setting, intravenous therapy with cyclosporine (2-4 mg/kg/day as a continuous infusion, and achieving blood levels of 250-450 ng/ml) appears to be favored, limiting time of therapy to 7-10 days. It should be noted, however, that in the controlled clinical trial of cyclosporine in adults with ulcerative colitis conducted by Lichtiger et al. (12), the dose of intravenously administered cyclosporine was 4 mg/kg/day, producing blood levels of 339-653 ng/ml. Use of Intravenous Azathioprine Loading Active Crohn's disease, and to a lesser extent, ulcerative colitis, which are refractory to standard medical therapy, are often treated with 6-MP or its prodrug, azathioprine. Dr. Sandborn pointed out that the widespread use of 6-MP and azathioprine as treatment for patients with severe disease has been limited by the prolonged time to response observed in adults and children (13–15). Nevertheless, the efficacy of adjunctive treatment with these agents was clearly demonstrated in controlled clinical trials and a recent meta-analysis of both active and maintenance therapy (16). Furthermore, the odds ratio of a response increases with the cumulative dose administered. It is known that the therapeutic efficacy (as well as the toxicity) of 6-MP and azathioprine depend on their metabolism to 6-thioguanine nucleotides (6-TGNs). A key metabolic enzyme, thiopurine methyltransferase (TPMT), is subject to significant genetic variation; individuals with low erythrocyte activity are at increased risk of severe toxicity or death (17–20). In patients with Crohn's disease and ulcerative colitis treated with these drugs, the prolonged and variable time required to reach a steady-state concentration of the 6-TGNs may correlate with the prolonged time required before a therapeutic response occurs. These observations suggest that administration of an i.v. loading dose of 6-MP or azathioprine may be useful to reduce the time to therapeutic efficacy. Indeed, a recently reported pilot study of i.v. loading of azathioprine in patients with Crohn's disease confirms this hypothesis (15), as a considerably more rapid response was achieved. All patients were tested for TPMT status before receiving the drug. At present, there are no studies of i.v. loading of either 6-MP or azathioprine in the treatment of severe/fulminant colitis. Surgery in the Treatment of Severe Colitis When medical treatment fails to achieve remission in patients with severe or fulminant inflammatory bowel disease, surgery is routinely recommended. Dr. Doody discussed the indications and available surgical options for patients in this clinical setting. The choice of operation depends on the severity of illness and condition of the patient at the time of surgery. Total abdominal colectomy with formation of a Hartmann pouch and end ileostomy is the safest procedure for complicated ulcerative colitis, with an extremely low morbidity. This procedure has the advantage of removing the septic source in severe colitis with or without perforation. Oversewing the rectal pouch is typically not associated with extension of inflammation through the rectal musculature and into the pelvis. At a second operation, a more definitive procedure can be performed. This approach is also often most appropriate for cases of indeterminate colitis. Total proctocolectomy with ileostomy would generally not be recommended for active severe ulcerative colitis. However, this procedure might be indicated for severe Crohn's colitis, especially if accompanied by significant rectal involvement and perianal disease. However, the extent of pelvic dissection in the face of severe colitis increases the risk of late complications related to the genitourinary tract. In general, during acute and severe colitis, total abdominal colectomy with preservation of the rectum is performed. The pull-through operation in the treatment of chronic ulcerative colitis has become the procedure of choice for most pediatric surgeons, by using either a J or an S pouch with a defunctionalizing ileostomy. This procedure is generally not the approach of choice in severe active disease. Some surgeons perform this procedure without the ileostomy for moderately active disease when surgery is elective or semielective. It would be inappropriate to do this procedure in children who are systemically ill, receiving prolonged courses of steroids, or have hypoalbuminemia or malnutrition. Surgical complications include technical events related to the procedure, recurrence of disease at the site of the anastomosis (Crohn's disease), enterocutaneous fistulas, perforation at the anastomotic site, rectal cuff abscess, or rectal stricture (21,22). Conclusions Severe or fulminant colitis may occur in either ulcerative colitis or Crohn's disease. Criteria for the diagnosis of severe colitis remain as published (3). Vigorous medical therapy is indicated but should be carefully monitored so that it is not excessively prolonged. Cyclosporine appears to be safe and effective as first-line treatment of severe ulcerative colitis and may be valuable in some patients with Crohn's colitis; however, potential complications must be considered. A team approach should be used in the management of severely ill patients with inflammatory bowel disease, and the pediatric surgeon should be involved early in the course. When it is clear that medical therapy is unlikely to achieve remission, appropriate surgical therapy should be instituted promptly. References 1.Truelove SC, Witts LJ. Cortisone in ulcerative colitis final report on a therapeutic trial. Br Med J 1955;2:1041-8. 2.Travis SP, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut 1996;38:905-10. 3.Werlin SL, Grand RJ. Severe colitis in children and adolescents: diagnosis, course, and treatment. Gastroenterology 1979;73:828-32. 4.Gold DM, Levine JJ, Weinstein TA, et al. Prolonged medical therapy for severe pediatric ulcerative colitis. Am J Gastroenterol 1995;97:732-5. 5.Sandborn WJ. A critical review of cyclosporin therapy in inflammatory bowel disease. Inflammatory Bowel Diseases 1995; 1:48-63. 6.Benkov KJ, Rosh JR, Schwersenz AH, et al. Cyclosporine as an alternative to surgery in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1994;19:290-4. 7.Treem WR, Cohen J, Davis PM, Justinich CJ, Hyams JS. Cyclosporine for the treatment of fulminant ulcerative colitis in children: immediate response, long-term results, and impact on surgery. Dis Colon Rectum 1995;38:474-9. 8.Ramakrishna JR, Langhans N, Calenda K, Grand RJ, Verhave M. Combined use of cyclosporine and azathioprine or 6-mercaptopurine in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1996;22:296-302. 9.Mahdi G, Israel DM, Hassall E. Cyclosporine and 6-mercaptopurine for active, refractory Crohn's colitis in children. Am J Gastroenterol 1996;91:1355-9. 10.Sandborn WJ, Goldman DH, Lawson GM, et al. Measurement of colonic tissue cyclosporine concentration in children with severe ulcerative colitis. J Pediatr Gastroenterol Nutr 1992;15: 125-9. 11.Kirschner BS, Whitington PF, Malfeo-Klein R. Experience with cyclosporin A in severe non-specific ulcerative colitis. Pediatr Res 1989;25:117A. 12.Lichitger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994; 330:1841-5. 13.Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr 1990;117: 809-14. 14.Markowitz J, Rosa J, Grancher K, Aiges H, Daum F. Long-term 6-mercaptopurine treatment in adolescents with Crohn's disease. Gastroenterology 1990;99:1347-51. 15.Sandborn WJ, Van Os EC, Zins BJ, Tremaine WJ, Mays DC, Lipsky JJ. An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn's disease. Gastroenterology 1995;109:1808-917. 16.Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn's disease: a meta-analysis. Ann Intern Med 1995;122:132-42. 17.Lennard L, Van Loon JA, Weinshilboum RN. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989;46:149-54. 18.Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RN. Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyl transferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther 1987;41:18-25. 19.Anstey A, Lennard L, Mayou SC, Kirby JD. Pancytopenia related to azathioprine: an enzyme deficiency caused by a common genetic polymorphism: a review. J R Soc Med 1992;85:752-6. 20.Cuffari C, Theoret Y, Latour S, Seidman EG. 6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity. Gut 1996;39:401-6. 21.Orkin BA, Telander RL, Wolff BG, Perrault J, Ilstrup DM. The surgical management of children with ulcerative colitis: the old vs the new. Dis Colon Rectum 1990;33:947-55. 22.Telander R. Surgical management of Crohn's disease in children. Curr Opin Pediatr 1995;7:328-34. © 1998 Crohn's & Colitis Foundation of America, Inc. © 1998 Crohn's & Colitis Foundation of America, Inc.
TI - Controversies in Pediatric Inflammatory Bowel Disease
JO - Inflammatory Bowel Diseases
DO - 10.1097/00054725-199808000-00005
DA - 1998-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/controversies-in-pediatric-inflammatory-bowel-disease-AtP2pV7obJ
SP - 203
EP - 227
VL - 4
IS - 3
DP - DeepDyve
ER -