nach oben

Erschienen in:

01.01.2009 | Original Article

Disease Behavior in Children with Crohn’s Disease: The Effect of Disease Duration, Ethnicity, Genotype, and Phenotype

verfasst von: Ron Shaoul, Amir Karban, Shimon Reif, Batia Weiss, Raanan Shamir, Ada Tamir, Ofir Davidovich, Jonathan Halevi, Esther Leshinsky Silver, Arie Levine

Erschienen in: Digestive Diseases and Sciences | Ausgabe 1/2009

Einloggen, um Zugang zu erhalten

Abstract

Background Disease behavior in Crohn’s disease (CD) may be modified by disease location and genotype. Disease behavior may change over time, and thus analysis requires follow-up. To date, there have been few pediatric studies that have evaluated the association between disease behavior and genotype with prolonged follow-up. The aim of our study was to evaluate the effect of genotype, phenotype, and ethnicity on disease behavior in pediatric CD. Methods Evaluation of 128 pediatric CD was followed by analysis of 232 pediatric and adult-onset CD patients. Inclusion required at least 2 years of follow-up. Phenotype, ethnicity, and disease duration were recorded. Patients were genotyped for polymorphisms in the NOD2/CARD15 gene. Results Colonic involvement was more frequent in younger patients. Pediatric disease at end of follow-up was classified as inflammatory (78%), penetrating (7%), and stricturing (17%). Duration of follow-up (mean 4.9 pediatric and 6.4 years mixed) was associated with more stricturing and penetrating disease. There was no association between mean age of onset and NOD2/CARD15, or either of these with disease behavior. These observations were replicated in the mixed cohort. Sephardic Jewish origin was inversely correlated with inflammatory behavior (P = 0.006), independent of NOD2/CARD15 genotype. Conclusions Duration of disease and ethnicity, irrespective of NOD2/CARD15 genotype and age of onset, were the only predictors for penetrating or stricturing disease.

Fiocchi C (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115:182–205. doi:10.1016/S0016-5085(98)70381-6 PubMedCrossRef

Podolsky DK (2002) Inflammatory bowel disease. N Engl J Med 347:417–429. doi:10.1056/NEJMra020831 PubMedCrossRef

Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K, Jewell DP, Karban A, Loftus EV Jr, Peña AS, Riddell RH, Sachar DB, Schreiber S, Steinhart AH, Targan SR, Vermeire S, Warren BF (2005) Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 19(Suppl A):5–36PubMed

Griffiths AM, Hugot JP (2004) Inflammatory bowel disease 1. Crohn disease. In: Walker WA, Goulet OJ, Kleinman RE, Sanderson IR, Sherman PM, Shneider BL, (eds) Pediatric gastrointestinal disease, 4th edn. BC Decker, pp 789–872

Bataille F, Klebl F, Rummele P, Schroeder J, Farkas S, Wild PJ, Fürst A, Hofstädter F, Schölmerich J, Herfarth H, Rogler G (2004) Morphological characterisation of Crohn’s disease fistulae. Gut 53:1314–1321. doi:10.1136/gut.2003.038208 PubMedCrossRef

Gasche C, Grundtner P (2005) Genotypes and phenotypes in Crohn’s disease: do they help in clinical management? Gut 54:162–167. doi:10.1136/gut.2003.035600 PubMedCrossRef

Gasche C, Scholmerich J, Brynskov J, D’Haens G, Hanauer SB, Irvine EJ, Jewell DP, Rachmilewitz D, Sachar DB, Sandborn WJ, Sutherland LR (2000) A simple classification of Crohn’s disease: report of the working party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 6:8–15PubMed

Cosnes J, Cattan S, Blain A, Beaugerie L, Carbonnel F, Parc R, Gendre JP (2002) Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis 8:244–250. doi:10.1097/00054725-200207000-00002 PubMedCrossRef

Louis E, Collard A, Oger AF, Degroote E, Aboul Nasr El Yafi FA, Belaiche J (2001) Behaviour of Crohn’s disease according to the Vienna classification: changing pattern over the course of the disease. Gut 49:777–782. doi:10.1136/gut.49.6.777 PubMedCrossRef

10.

Veloso FT, Ferreira JT, Barros L, Almeida S (2001) Clinical outcome of Crohn’s disease: analysis according to the vienna classification and clinical activity. Inflamm Bowel Dis 7:306–313. doi:10.1097/00054725-200111000-00005 PubMedCrossRef

11.

Freeman HJ (2004a) Comparison of longstanding pediatric-onset and adult-onset Crohn’s disease. J Pediatr Gastroenterol Nutr 39:183–186. doi:10.1097/00005176-200408000-00011 PubMedCrossRef

12.

Freeman HJ (2004b) Long-term prognosis of early-onset Crohn’s disease diagnosed in childhood or adolescence. Can J Gastroenterol 18:661–665PubMed

13.

Russell RK, Drummond HE, Nimmo EE, Anderson N, Smith L, Wilson DC, Gillett PM, McGrogan P, Hassan K, Weaver LT, Bisset M, Mahdi G, Satsangi J (2005) Genotype–phenotype analysis in childhood-onset Crohn’s disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease. Inflamm Bowel Dis 11:955–964. doi:10.1097/01.MIB.0000183423.38037.f3 PubMedCrossRef

14.

Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG (2001) Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 357:1925–1928. doi:10.1016/S0140–6736(00)05063-7 PubMedCrossRef

15.

Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603. doi:10.1038/35079107 PubMedCrossRef

16.

Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606. doi:10.1038/35079114 PubMedCrossRef

17.

Abreu MT, Taylor KD, Lin YC, Hang T, Gaiennie J, Landers CJ, Vasiliauskas EA, Kam LY, Rojany M, Papadakis KA, Rotter JI, Targan SR, Yang H (2002) Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn’s disease. Gastroenterology 123:79–88. doi:10.1053/gast.2002.35393 CrossRef

18.

Ahmad T, Armuzzi A, Bunce M, Mulcahy-Hawes K, Marshall SE, Orchard TR, Orchard TR, Crawshaw J, Large O, de Silva A, Cook JT, Barnardo M, Cullen S, Welsh KI, Jewell DP (2002) The molecular classification of the clinical manifestations of Crohn’s disease. Gastroenterology 122:854–866. doi:10.1053/gast.2002.32413 PubMedCrossRef

19.

Bairead E, Harmon DL, Curtis AM, Kelly Y, O’Leary C, Gardner M, Leahy DT, Vaughan P, Keegan D, O’Morain C, O’Donoghue D, Shanahan F, Parfrey NA, Quane KA (2003) Association of NOD2 with Crohn’s disease in a homogenous Irish population. Eur J Hum Genet 11:237–244. doi:10.1038/sj.ejhg.5200954 PubMedCrossRef

20.

Cuthbert AP, Fisher SA, Mirza MM, King K, Hampe J, Croucher PJ, Mascheretti S, Sanderson J, Forbes A, Mansfield J, Schreiber S, Lewis CM, Mathew CG (2002) The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. Gastroenterology 122:867–874. doi:10.1053/gast.2002.32415 PubMedCrossRef

21.

Giachino D, van Duist MM, Regazzoni S, Gregori D, Bardessono M, Salacone P, Scaglione N, Sostegni R, Sapone N, Bresso F, Sambataro A, Gaia E, Pera A, Astegiano M, De Marchi M (2004) Analysis of the CARD15 variants R702W, G908R and L1007fs in Italian IBD patients. Eur J Hum Genet 12:206–212. doi:10.1038/sj.ejhg.5201130 PubMedCrossRef

22.

Hampe J, Grebe J, Nikolaus S, Solberg C, Croucher PJ, Mascheretti S, Jahnsen J, Moum B, Klump B, Krawczak M, Mirza MM, Foelsch UR, Vatn M, Schreiber S (2002) Association of NOD2 (CARD 15) genotype with clinical course of Crohn’s disease: a cohort study. Lancet 359:1661–1665. doi:10.1016/S0140-6736(02)08590-2 PubMedCrossRef

23.

Helio T, Halme L, Lappalainen M, Fodstad H, Paavola-Sakki P, Turunen U, Färkkilä M, Krusius T, Kontula K (2003) CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn’s disease. Gut 52:558–562. doi:10.1136/gut.52.4.558 PubMedCrossRef

24.

Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O’Morain C, Gassull M, Binder V, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Merlin F, Chamaillard M, Jannot AS, Thomas G, Hugot JP (2002) CARD15/NOD2 mutational analysis and genotype–phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 70:845–857. doi:10.1086/339432 PubMedCrossRef

25.

Mendoza JL, Murillo LS, Fernandez L, Pena AS, Lana R, Urcelay E, Cruz-Santamaría DM, de la Concha EG, Díaz-Rubio M, García-Paredes J (2003) Prevalence of mutations of the NOD2/CARD15 gene and relation to phenotype in Spanish patients with Crohn disease. Scand J Gastroenterol 38:1235–1240. doi:10.1080/00365520310006612 PubMedCrossRef

26.

Vermeire S, Wild G, Kocher K, Cousineau J, Dufresne L, Bitton A, Langelier D, Pare P, Lapointe G, Cohen A, Daly MJ, Rioux JD (2002) CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. Am J Hum Genet 71:74–83. doi:10.1086/341124 PubMedCrossRef

27.

Brant SR, Picco MF, Achkar JP, Bayless TM, Kane SV, Brzezinski A, Nouvet FJ, Bonen D, Karban A, Dassopoulos T, Karaliukas R, Beaty TH, Hanauer SB, Duerr RH, Cho JH (2003) Defining complex contributions of NOD2/CARD15 gene mutations, age at onset, and tobacco use on Crohn’s disease phenotypes. Inflamm Bowel Dis. 9:281–289. doi:10.1097/00054725-200309000-00001 PubMedCrossRef

28.

Economou M, Trikalinos TA, Loizou KT, Tsianos EV, Ioannidis JP (2004) Differential effects of NOD2 variants on Crohn’s disease risk and phenotype in diverse populations: a metaanalysis. Am J Gastroenterol 99:2393–2404. doi:10.1111/j.1572-0241.2004.40304.x PubMedCrossRef

29.

Radlmayr M, Torok HP, Martin K, Folwaczny C (2002) The c-insertion mutation of the NOD2 gene is associated with fistulizing and fibrostenotic phenotypes in Crohn’s disease. Gastroenterology 122:2091–2092. doi:10.1053/gast.2002.34020 PubMedCrossRef

30.

Brand S, Staudinger T, Schnitzler F, Pfennig S, Hofbauer K, Dambacher J, Seiderer J, Tillack C, Konrad A, Crispin A, Göke B, Lohse P, Ochsenkühn T (2005) The role of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn’s disease. Inflamm Bowel Dis 11:645–652. doi:10.1097/01.MIB.0000168372.94907.d2 PubMedCrossRef

31.

Smith BR, Arnott ID, Drummond HE, Nimmo ER, Satsangi J (2004) Disease location, anti-Saccharomyces cerevisiae antibody, and NOD2/CARD15 genotype influence the progression of disease behavior in Crohn’s disease. Inflamm Bowel Dis 10:521–528. doi:10.1097/00054725-200409000-00005 PubMedCrossRef

32.

Heyman MB, Kirschner BS, Gold BD, Ferry G, Baldassano R, Cohen SA, Winter HS, Fain P, King C, Smith T, El-Serag HB (2005) Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium registry. J Pediatr 146:35–40. doi:10.1016/j.jpeds.2004.08.043 PubMedCrossRef

33.

Levine A, Karban A, Eliakim R, Shaoul R, Reif S, Pacht A, Wardi J, Yakir B, Silver EL (2005) A polymorphism in the TNF-alpha promoter gene is associated with pediatric onset and colonic location of Crohn’s disease. Am J Gastroenterol 100:407–413. doi:10.1111/j.1572-0241.2005.41126.x PubMedCrossRef

34.

Mamula P, Telega GW, Markowitz JE, Brown KA, Russo PA, Piccoli DA, Baldassano RN (2002) Inflammatory bowel disease in children 5 years of age and younger. Am J Gastroenterol 97:2005–2010. doi:10.1111/j.1572-0241.2002.05915.x PubMedCrossRef

35.

Meinzer U, Idestrom M, Alberti C, Peuchmaur M, Belarbi N, Bellaiche M, Mougenot JF, Cézard JP, Finkel Y, Hugot JP (2005) Ileal involvement is age dependent in pediatric Crohn’s disease. Inflamm Bowel Dis 11:639–644. doi:10.1097/01.MIB.0000165114.10687.bf PubMedCrossRef

36.

Sawczenko A, Sandhu BK (2003) Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child 88:995–1000. doi:10.1136/adc.88.11.995 PubMedCrossRef

37.

Levine A, Kugathasan S, Annese V, Biank V, Leshinsky-Silver E, Davidovich O, Kimmel G, Shamir R, Orazio P, Karban A, Broeckel U, Cucchiara S (2007) Pediatric onset Crohn’s colitis is characterized by genotype-dependent age-related susceptibility. Inflamm Bowel Dis 13:1509–1515. doi:10.1002/ibd.20244 PubMedCrossRef

38.

Inflammatory bowel disease in children and adolescents: recommendations for diagnosis—the Porto criteria. J Pediatr Gastroenterol Nutr (2005) 41:1–7. doi:10.1097/01.MPG.0000163736.30261.82

39.

Karban A, Itay M, Davidovich O, Leshinsky-Silver E, Kimmel G, Fidder H, Shamir R, Waterman M, Eliakim R, Levine A (2007) Risk factors for perianal Crohn’s disease: the role of genotype, phenotype, and ethnicity. Am J Gastroenterol 102:1702–1708. doi:10.1111/j.1572-0241.2007.01277.x PubMedCrossRef

40.

Ahmadian A, Gharizadeh B, Gustafsson AC, Sterky F, Nyren P, Uhlen M, Lundeberg J (2000) Single-nucleotide polymorphism analysis by pyrosequencing. Anal Biochem 280:103–110. doi:10.1006/abio.2000.4493 PubMedCrossRef

41.

Shaoul R, Karban A, Weiss B, Reif S, Wasserman D, Pacht A, Eliakim R, Wardi J, Shirin H, Wine E, Leshinsky-Silver E, Levine A (2004) NOD2/CARD15 mutations and presence of granulomas in pediatric and adult Crohn’s disease. Inflamm Bowel Dis 10:709–714. doi:10.1097/00054725-200411000-00003 PubMedCrossRef

42.

Zhang K, Deng M, Chen T, Waterman MS, Sun F (2002) A dynamic programming algorithm for haplotype block partitioning. Proc Natl Acad Sci USA 99:7335–7339. doi:10.1073/pnas.102186799 PubMedCrossRef

43.

Kugathasan S, Judd RH, Hoffmann RG, Heikenen J, Telega G, Khan F, Weisdorf-Schindele S, San Pablo W Jr, Perrault J, Park R, Yaffe M, Brown C, Rivera-Bennett MT, Halabi I, Martinez A, Blank E, Werlin SL, Rudolph CD, Binion DG (2003) Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: a statewide population-based study. J Pediatr 143:525–531. doi:10.1067/S0022-3476(03)00444-X PubMedCrossRef

44.

Sun L, Roesler J, Rosen-Wolff A, Winkler U, Koch R, Thurigen A, Henker J (2003) CARD15 genotype and phenotype analysis in 55 pediatric patients with Crohn disease from Saxony, Germany. J Pediatr Gastroenterol Nutr 37:492–497. doi:10.1097/00005176-200310000-00017 PubMedCrossRef

45.

Griffiths AM, Nguyen P, Smith C, MacMillan JH, Sherman PM (1993) Growth and clinical course of children with Crohn’s disease. Gut 34:939–943. doi:10.1136/gut.34.7.939 PubMedCrossRef

46.

Newman B, Silverberg MS, Gu X, Zhang Q, Lazaro A, Steinhart AH, Greenberg GR, Griffiths AM, McLeod RS, Cohen Z, Fernández-Viña M, Amos CI, Siminovitch K (2004) CARD15 and HLA DRB1 alleles influence susceptibility and disease localization in Crohn’s disease. Am J Gastroenterol 99:306–315. doi:10.1111/j.1572-0241.2004.04038.x PubMedCrossRef

47.

Arnott ID, Nimmo ER, Drummond HE, Fennell J, Smith BR, MacKinlay E, Morecroft J, Anderson N, Kelleher D, O’Sullivan M, McManus R, Satsangi J (2004) NOD2/CARD15, TLR4 and CD14 mutations in Scottish and Irish Crohn’s disease patients: evidence for genetic heterogeneity within Europe? Genes Immun 5:417–425. doi:10.1038/sj.gene.6364111 PubMedCrossRef

48.

Hildebrand H, Finkel Y, Grahnquist L, Lindholm J, Ekbom A, Askling J (2003) Changing pattern of paediatric inflammatory bowel disease in northern Stockholm 1990–2001. Gut 52:1432–1434. doi:10.1136/gut.52.10.1432 PubMedCrossRef

49.

Idestrom M, Rubio C, Granath F, Finkel Y, Hugot JP (2005) CARD15 mutations are rare in Swedish pediatric Crohn disease. J Pediatr Gastroenterol Nutr 40:456–460. doi:10.1097/01.MPG.0000150423.38210.2E PubMedCrossRef

50.

Russell RK, Wilson DC, Satsangi J (2004) Unravelling the complex genetics of inflammatory bowel disease. Arch Dis Child 89:598–603. doi:10.1136/adc.2003.041046 PubMedCrossRef

51.

Tomer G, Ceballos C, Concepcion E, Benkov KJ (2003) NOD2/CARD15 variants are associated with lower weight at diagnosis in children with Crohn’s disease. Am J Gastroenterol 98:2479–2484. doi:10.1111/j.1572-0241.2003.08673.x PubMedCrossRef

52.

Bueno De Mesquita M, Ferrante M, Joossens M, De Assche G, Vermeire S, Rutgeerts P, Janssens V, Hoffman I (2005) Study on CARD15 and TLR4 polymorphisms in children with early diagnosed ibd. J Pediatr Gastroenterol Nutr 40:640. doi:10.1097/00005176-200505000-00089

53.

Kugathasan S, Collins N, Maresso K, Hoffmann RG, Stephens M, Werlin SL, Rudolph C, Broeckel U (2004) CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn’s disease. Clin Gastroenterol Hepatol 2:1003–1009. doi:10.1016/S1542-3565(04)00452-5 PubMedCrossRef

Titel: Disease Behavior in Children with Crohn’s Disease: The Effect of Disease Duration, Ethnicity, Genotype, and Phenotype
verfasst von: Ron Shaoul
Amir Karban
Shimon Reif
Batia Weiss
Raanan Shamir
Ada Tamir
Ofir Davidovich
Jonathan Halevi
Esther Leshinsky Silver
Arie Levine
Publikationsdatum: 01.01.2009
Verlag: Springer US
Erschienen in: Digestive Diseases and Sciences / Ausgabe 1/2009
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-008-0326-7

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Reizdarmsyndrom: Diäten wirksamer als Medikamente

29.04.2024 Reizdarmsyndrom Nachrichten

Bei Reizdarmsyndrom scheinen Diäten, wie etwa die FODMAP-arme oder die kohlenhydratreduzierte Ernährung, effektiver als eine medikamentöse Therapie zu sein. Das hat eine Studie aus Schweden ergeben, die die drei Therapieoptionen im direkten Vergleich analysierte.

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2009

Progression of Hypermethylation of the p16 INK4A Gene from Normal Liver to Nontumorous Liver and Hepatocellular Carcinoma: An Evaluation Using Quantitative PCR Analysis

Octreotide Uptake in Intracranial Metastasis of Pancreatic Ductal Adenocarcinoma Origin in a Patient with a Prolonged Clinical Course

It Is Possible to Classify Non-erosive Reflux Disease (NERD) Patients into Endoscopically Normal Groups and Minimal Change Groups by Subjective Symptoms and Responsiveness to Rabeprazole—A Report from a Study with Japanese Patients

siRNA Directed Against Survivin Enhances Pancreatic Cancer Cell Gemcitabine Chemosensitivity

Gastroenterology Research Group and Digestive Diseases and Sciences