Inflammatory bowel disease in patients with congenital chloride diarrhoea

[en] Introduction: Congenital chloride diarrhoea (CLD) is a rare autosomal recessive disease caused by mutations in the solute family carrier 26 member 3 (SLC26A3) gene. Patients suffer from life-long watery diarrhea and chloride loss. Inflammatory bowel disease (IBD) has been reported in individual patients with CLD and in scl26a3-deficient mice. Methods: We performed an international multicentre analysis to build a CLD cohort and to identify cases with IBD. We assessed clinical and genetic characteristics of subjects and studied the cumulative incidence of CLD-associated IBD. Results: In a cohort of 72 patients with CLD caused by 17 different SLC26A3 mutations, we identified 12 patients (17%) diagnosed with IBD. Nine patients had Crohn's disease, two ulcerative colitis, and one IBD-unclassified (IBD-U). Prevalence of IBD in our cohort of CLD is higher than the highest prevalence of IBD in Europe (p < 0.0001). The age of onset was variable (13.5 years, IQR: 8.5 - 23.5 years). Patients with CLD and IBD had lower z-score for height than those without IBD. 4/12 patients had required surgery (ileostomy formation n=2, ileocaecal resection due to ileocaecal valve stenosis n=1, and colectomy due to stage II transverse colon cancer n=1). At last follow-up, 5/12 were on biologics (adalimumab, infliximab, or vedolizumab), 5/12 on immunosuppressant (azathioprine or mercaptopurine), one on 5-ASA and one off-treatment. Conclusions: A substantial proportion of patients with CLD develop IBD. This suggests potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.

Disciplines :

Gastroenterology & hepatology

Author, co-author :

Norsa, Lorenzo; ‎Ospedale papa Giovanni XXIII, bergamo > Gastroentérologie pédiatrique

Berni Canani, Roberto

Duclaux-Loras, Rémi

Bequet, Emeline ; Centre Hospitalier Universitaire de Liège - CHU > Département de Pédiatrie > Service de pédiatrie

Köglmeier, Jutta

Russell, Richard K

Uhlig, Holm

Travis, Simon

Hollis, Jennifer

Koletzko, Sibylle

More authors (14 more)

Language :

English

Title :

Inflammatory bowel disease in patients with congenital chloride diarrhoea

Publication date :

26 March 2021

Journal title :

Journal of Crohn's and Colitis

ISSN :

1873-9946

eISSN :

1876-4479

Publisher :

Elsevier, United Kingdom

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 25 May 2021

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Bibliography

Evanson JM, Stanbury SW. Congenital chloridorrhoea or so-called congenital alkalosis with diarrhoea. Gut 1965;6:29-38.
Darrow DC. Congenital alkalosis with diarrhea. J Pediatr 1945;26:519-32.
Wedenoja S, Höglund P, Holmberg C. Review article: The clinical management of congenital chloride diarrhoea. Aliment Pharmacol Ther 2010;31:477-85.
Wedenoja S, Pekansaari E, Höglund P, Mäkelä S, Holmberg C, Kere J. Update on SLC26A3 mutations in congenital chloride diarrhea. Hum Mutat 2011;32:715-22.
Amato F, Cardillo G, Liguori R, et al. Twelve novel mutations in the SLC26A3 gene in 17 sporadic cases of congenital chloride diarrhea. J Pediatr Gastroenterol Nutr 2017;65:26-30.
Höglund P, Haila S, Socha J, et al. Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nat Genet 1996;14:316-9.
Schweinfest CW, Spyropoulos DD, Henderson KW, et al. slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon. J Biol Chem 2006;281:37962-71.
Holmberg C, Perheentupa J, Launiala K, Hallman N. Congenital chloride diarrhoea. Clinical analysis of 21 Finnish patients. Arch Dis Child 1977;52:255-67.
Kamal NM, Khan HY, El-Shabrawi MHF, Sherief LM. Congenital chloride losing diarrhea: a single center experience in a highly consanguineous population. Medicine 2019;98:e15928.
Hihnala S, Höglund P, Lammi L, Kokkonen J, Ormälä T, Holmberg C. Long-term clinical outcome in patients with congenital chloride diarrhea. J Pediatr Gastroenterol Nutr 2006;42:369-75.
Kurteva E, Lindley KJ, Hill SM, Köglmeier J. Mucosal abnormalities in children with congenital chloride diarrhea-an underestimated phenotypic feature? Front Pediatr 2020;8:365.
Harris RE, Tayler R, Russell RK. Congenital chloride-losing diarrhoea and Crohn's disease: a diagnostic and therapeutic challenge. Frontline Gastroenterol 2019;12:151-3.
Yang H, Jiang W, Furth EE, et al. Intestinal inflammation reduces expression of DRA, a transporter responsible for congenital chloride diarrhea. Am J Physiol 1998;275:G1445-53.
Gill RK, Borthakur A, Hodges K, et al. Mechanism underlying inhibition of intestinal apical Cl/OH exchange following infection with enteropathogenic E. coli. J Clin Invest 2007;117:428-37.
Borenshtein D, Schlieper KA, Rickman BH, et al. Decreased expression of colonic Slc26a3 and carbonic anhydrase iv as a cause of fatal infectious diarrhea in mice. Infect Immun 2009;77:3639-50.
Asano K, Matsushita T, Umeno J, et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 2009;41:1325-9.
Levine A, Koletzko S, Turner D, et al.; European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr 2014;58:795-806.
Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 2011;17:1314-21.
Uhlig HH, Schwerd T, Koletzko S, et al.; COLORS in IBD Study Group and NEOPICS. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 2014;147:990-1007.e3.
Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46-54.e42; quiz e30.
Wedenoja S, Khamaysi A, Shimshilashvili L, et al. A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR. Sci Rep 2017;7:14208.
Momozawa Y, Dmitrieva J, Theátre E, et al. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nat Commun 2018;9:2427.
de Bie CI, Buderus S, Sandhu BK, et al.; EUROKIDS Porto IBD Working Group of ESPGHAN. Diagnostic workup of paediatric patients with inflammatory bowel disease in Europe: results of a 5-year audit of the EUROKIDS registry. J Pediatr Gastroenterol Nutr 2012;54:374-80.
Buderus S, Scholz D, Behrens R, et al.; CEDATA-GPGE Study Group. Inflammatory bowel disease in pediatric patients: characteristics of newly diagnosed patients from the CEDATA-GPGE Registry. Dtsch Arztebl Int 2015;112:121-7.
Höglund P, Haila S, Socha J, et al. Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nat Genet 1996;14:316-9.
Silberg DG, Wang W, Moseley RH, Traber PG. The Down regulated in Adenoma (dra) gene encodes an intestine-specific membrane sulfate transport protein. J Biol Chem 1995;270:11897-902.
Schweinfest CW, Spyropoulos DD, Henderson KW, et al. slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon. J Biol Chem 2006;281:37962-71.
Xiao F, Yu Q, Li J, et al. Slc26a3 deficiency is associated with loss of colonic HCO3 secretion, absence of a firm mucus layer and barrier impairment in mice. Acta Physiol 2014;211:161-75.
Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012;486:207-14.
Conlon MA, Bird AR. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 2014;7:17-44.
Xiao F, Juric M, Li J, et al. Loss of downregulated in adenoma (DRA) impairs mucosal HCO3 secretion in murine ileocolonic inflammation. Inflamm Bowel Dis 2012;18:101-11.
Juric M, Xiao F, Amasheh S, et al. Increased epithelial permeability is the primary cause for bicarbonate loss in inflamed murine colon. Inflamm Bowel Dis 2013;19:904-11.
Kumar A, Chatterjee I, Gujral T, et al. Activation of nuclear factorB by tumor necrosis factor in intestinal epithelial cells and mouse intestinal epithelia reduces expression of the chloride transporter SLC26A3. Gastroenterology 2017;153:1338-50.e3.
Ding X, Li D, Li M, Tian D, Yu H, Yu Q. Tumor necrosis factor acts reciprocally with solute carrier family 26, member 3, (downregulated-inadenoma) and reduces its expression, leading to intestinal inflammation. Int J Mol Med 2018;41:1224-32.
Laubitz D, Larmonier CB, Bai A, et al. Colonic gene expression profile in NHE3-deficient mice: Evidence for spontaneous distal colitis. Am J Physiol Gastrointest Liver Physiol 2008;295:G63-77.
Janecke AR, Heinz-Erian P, Yin J, et al. Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. Hum Mol Genet 2015;24:6614-23.
Müller T, Rasool I, Heinz-Erian P, et al. Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C. Gut 2016;65:1306-13.
Harris RA, Shah R, Hollister EB, et al. Colonic mucosal epigenome and microbiome development in children and adolescents. J Immunol Res 2016;2016:9170162.
Miranda PM, De Palma G, Serkis V, et al. High salt diet exacerbates colitis in mice by decreasing Lactobacillus levels and butyrate production. Microbiome 2018;6:57.
Wilck N, Matus MG, Kearney SM, et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 2017;551:585-9.
Ishige T. Growth failure in pediatric onset inflammatory bowel disease: mechanisms, epidemiology, and management. Transl Pediatr 2019;8:16-22.
Trier Moller F, Andersen V, Andersson M, Jess T. Hospital admissions, biological therapy, and surgery in familial and sporadic cases of inflammatory bowel disease: a population-based cohort study 1977-2011. Inflamm Bowel Dis 2015;21:2825-32.
Turunen P, Ashorn M, Auvinen A, Iltanen S, Huhtala H, Kolho KL. Long-term health outcomes in pediatric inflammatory bowel disease: a population-based study. Inflamm Bowel Dis 2009;15:56-62.
Canani RB, Terrin G, Cirillo P, et al. Butyrate as an effective treatment of congenital chloride diarrhea. Gastroenterology 2004;127:630-4.
Larmonier CB, Laubitz D, Hill FM, et al. Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice. Am J Physiol Gastrointest Liver Physiol 2013;305:G667-77.
Svolos V, Hansen R, Nichols B, et al. Treatment of active Crohn's disease with an ordinary food-based diet that replicates exclusive enteral nutrition. Gastroenterology 2019;156:1354-67.e6.