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European Review for Medical and Pharmacological Sciences 2006; 10: 127-130 Crohn’s disease and celiac disease: association or epiphenomenon?

A. TURSI, G.M. GIORGETTI*, G. BRANDIMARTE**, W. ELISEI**

Digestive Unit, “Lorenzo Bonomo” Hospital – Andria, BA (Italy) *Department of , Clinical Nutrition Unit, “S. Eugenio” Hospital – Rome (Italy) **Department of Internal Medicine, Division of , “Cristo Re” Hospital – Rome (Italy)

Abstract. – Recent literature data show tive study: about 18% of patients affected by a certain relation between Crohn’s disease and Crohn’s disease are also affected by celiac celiac disease. We describe herein what are 8 the pro and the cons about a possible associa- disease . tion between Crohn’s disease and celiac dis- But why there is a so strict relation? It is a ease. real association or celiac disease-like lesions in Crohn’s disease should be considered as Key Words: epiphenomenon? Celiac disease, Crohn’s disease.

Why to Investigate About Celiac Disease in Crohn’s Disease?

Diagnosis of celiac disease is often inci- Introduction dental. It is a common finding in clinical practice that in some cases of non-stenotic, Crohn’s disease is a chronic inflammatory non-fistulizing Crohn’s disease it is quite disease of bowel potentially affecting mainly difficult to obtain adequate control of diar- the terminal and proximal colon1. rhoea, despite exclusion of the most fre- Histopathologically, it is characterized by a quent causes of diarrhoea (as parasitic in- discontinuous segmental manifestation and festations or Clostridium difficile infection implication of all intestinal layers, while clini- due to long-course of antibiotics). In fact, in cally it is characterized by a typical malab- most of cases reported the diagnosis of celi- sorption syndrome2. ac disease in Crohn’s disease was due to not Celiac disease is a syn- reversible after an anti-inflamma- drome caused by -induced small in- tory therapy had started4-7. In light of these testinal damage. It is characterized by a flat- studies, we think that celiac disease should tened mucosa, villous and crypt hy- be always investigated in Crohn’s disease as perplasia in the and by mal- soon as possible. absorption syndrome (diarrhea, , ) or by minor apparently unrelat- ed symptoms such as iron-deficiency How to Investigate About Celiac Disease anaemia, osteopenic bone disease, amenor- in Crohn’s Disease rhea and infertility1. The lack of gluten in the diet generally leads to a return to nor- The first problem in clinical practice is how mality of the morphological changes3. to investigate about celiac disease in Crohn’s Some recent case reports4-7 showed that disease. This is an important point, since there is a certain relation between Crohn’s most of the common tests in celiac disease and celiac disease. These data have disease often fail (both as false positive and been recently confirmed by an our prospec- as false negative).

Corresponding Author: Antonio Tursi, MD; e-mail: [email protected] 127 A. Tursi, G.M. Giorgetti, G. Brandimarte, W. Elisei

Serological Tests silent form18. Unfortunately, we found sor- • Anti- (AGA) show poor bitol H2-BT effective in detecting small bowel specificity, since AGA can be found in 14- histological damage both in Crohn’s disease 16% of patients affected by Crohn’s dis- and celiac disease: so, we confirmed the low ease (and in absence of celiac disease)8. specificity of this test in detecting small bowel • Anti-endomysium antibodies (EMA) seem histological damage, since it did not differen- to be more interesting for high sensitivity tiate between the causes of intestinal and specificity. However, it need technical damage19. expertise lecture and the recent data about their low prevalence in clinical practice9 Endoscopy seems to limit their use as screening test in Endoscopic markers show an high positive Crohn’s disease. predicting value in diagnosing celiac dis- • Also anti-tissue (tTG) ease14,20. However, recently Culliford et al de- antibodies seem to be not useful. We found scribed some cases of duodenal Crohn’s dis- contrasting results in this field. In fact we ease mimicking the endoscopic aspects of found some cases of IBD patients showing celiac disease21. We failed to find duodenal anti-tTG positivity but not affected by celi- endoscopic damage related to Crohn’s dis- ac disease (personal communication), in ease and not to celiac disease: the data by line to other literature experiences10,11. On Culliford et al should be thus kept in mind, the other hand, we also failed to find anti- since the only endoscopic duodenal appear- tTG in patients affected by Crohn’s disease ance could be a confounding data for a not and celiac disease8. Two different hypothe- expert endoscopist. ses be made about this. First of all, this results may be in part related to the different diagnostic assay in assessing anti- Celiac Disease in Crohn’s Disease: tTG (human recombinant anti-tTG versus Immuno-Pathogenetic Hypothesis guinea pig liver anti-tTG)12. Second, the presence of anti-tTG in Crohn’s disease pa- We think that the immuno-pathogenesis of tients may be a consequence of the induc- both the diseases and in particular intraep- tion of an increased apoptosis in those re- ithelial T cells may be the key to explain this gions undergoing the destruction typical of association. The human severe celiac disease-associated lesions, possesses a complex echosystem, in which that is a common event in every chronic there is a correct balance between antigenic gastrointestinal disease13. stimuli and immune response. Chronic in- • Several patients affected by Crohn’s dis- flammatory intestinal disease are character- ease and celiac disease are seronegative for ized by an up-regulation of the immunologi- AGA, EMA and anti-tTG. This is particu- cal response, which may be T helper type 1 larly true for patients showing slight/mod- (Th1: stimulation of type 1 immunity, which is erate histological damage of characterized by intense phagocytic activity, (Marsh II-IIIa lesions)14,15. and moderate stimulation of antibodies) or type 2 (Th2: stimulation of type 2 immunity, H2 Breath Test which is characterized by suppression of Sorbitol, a hexahydroxy alcohol used as a phagocytic activity and high antibodies titers) sugar substitute in many dietetic foods and as immunologic response. Both Crohn’s disease a drug vehicle, has been recently used to di- and celiac disease are related to Th1 agnose celiac patients, since its supply at low pathway22, characterized by a decreased cel- dose and concentration to patients with celiac lular apoptosis, which provoke a chronic in- disease resulted in an increased excretion of flammation especially in the lamina propria23. 16 H2 with respect to healthy controls . It has This alteration is confirmed by caspase 8 re- been recently showed that this test may be duction24 and under expression of BAX useful as a screening tool in patients with celi- which favors apoptosis resistance of intraep- ac disease17, as well as we demonstrate its ef- ithelial T cells, as described in both these dis- fectiveness also in detecting histological le- eases25,26. These findings seem to be related to sions in the patients affected by subclinical/ IL-15 action. This cytokine shares biological

128 Crohn’s disease and celiac disease: association or epiphenomenon? activities but no significant sequence homolo- References gy with IL-2; it induces recruitment to site of , T cell proliferation, cy- 1) MARTUCCI S, BIAGI F, D I SABATINO A, CORAZZA GR. Coeliac disease. Digest Liver Dis 2002; 34 (Sup- tokines production and rescue from apopto- pl. 2): S150-S153. sis. IL-15 over-expression has been also 27-29 2) KEIGHLEY MR, STOCKBRUGGER RW. Inflammatory bow- demonstrated . Moreover, other cytokines el disease. Aliment Pharmacol Ther 2003; 18 involved in cell-mediated immuno-pathogen- (Suppl. 3): 66-70. esis (such as TNF-α, INF-γ or IL-8) are in- 22,30 3) CATASSI C, RATSCH IM, FABIANI E, ROSSIGNI M, MORDIC- creased in both diseases . All these data CHIA F, C ANDELA F, C OPPA GV, GIORGI PL. Coeliac dis- confirm the possible common immuno-patho- ease in the year 2000: exploring the iceberg. genesis of both diseases. Lancet 1994; 343: 200-203. Why not all Crohn’s disease patients devel- 4) TURSI A, GIORGETTI GM, BRANDIMARTE G, RUBINO E, op celiac disease? The first hypothesis is that LOMBARDI D, GASBARRINI G. Prevalence and clinical these diseases show different HLA suscepti- presentation of subclinical/silent coeliac disease bility. We know the strict relation between in adults: an analysis on a 12-year observation. Hepato-Gastroenterol 2001; 39: 462-464. celiac disease and HLA-DQ2 and HLA- DQ831, while the relation between Crohn’s 5) CHEIKH I, MAAMOURI N, CHOUAIB S, CHAABOUNI H, OUERGHI H, BEN AMMAR A. Association of celiac disease and HLA genes seems to be disease and Crohn’s disease. A case report. Tu- 32 lacking . So, only Crohn’s disease patients nis Med 2003; 81: 969-971. showing HLA-DQ2 or –DQ8 could develop 6) CHAKRABORTY A, BREMNER AR, MOORE I, BEATTIE RM. then also the celiac disease. Another more Coeliac disease and Crohn’s disease: an associ- intriguing hypothesis is related to the in- ation not to be forgotten. Hosp Med 2003; 64: creased gut permeability in these diseases. 684-685. Crohn’s disease is characterized by an in- 7) SCHEDEL J, ROCKMANN F, B ONGARTZ T, W OENCKHAUS M, creased gut permeability, which may be relat- SCHOLMERICH E, KULLMANN F. Association of Crohn’s ed to TNF-α action33, and it may provoke a disease and latent celiac disease: a case report bacterial translocation as consequence of the and review of the literature. Int J Colorectal Dis 2005; 20: 376-380. bacterial overgrowth34. Also the celiac dis- ease shows an increased gut permeability due 8) TURSI A, GIORGETTI GM, BRANDIMARTE G, ELISEI W. High prevalence of celiac disease among patients to reduction, a protein modeling in- affected by Crohn’s disease. Inflamm Bowel Dis testinal permeability between tight junc- 2005; 11: 662-666. tions35. The hypothesis explaining this associ- 9) TURSI A, BRANDIMARTE G, GIORGETTI GM, GIGLIOBIANCO ation may be the follows: the increased per- G, LOMBARDI D, GASBARRINI G. Low prevalence of meability in Crohn’s disease may expose sev- antigliadin (AGA) and anti-endomysium (EMA) eral bacteria mimicking the 57-68 and/or 62- antibodies in subclinical/silent celiac disease. Am 75 gliadin sequence, and able then, thanks to J Gastroenterol 2001; 96: 1507-1510. increasing of cytokines network (IL-15, Il-2, 10) BIZZARRO N, VILLALTA D, TONUTTI E, DORIA A, TAMPOIA TNF-α, INF-γ), to cause a Th1 immunologi- M, BASSETTI D, TOZZOLI R. IgA and IgG tissue trans- cal reaction with development of celiac dis- glutaminase prevalence and clinical sig- nificance in connective tissue diseases, inflam- ease lesions. This hypothesis seems con- matory bowel disease, and primary biliary cirrho- firmed by the recent demonstration of high sis. Dig Dis Sci 2003; 48: 2360-2365. seroreactivity against Saccharomyces cere- 11) DATELE AVM, ALDHOUS MC, HUMPHREYS K, GHOSH S. visiae not only in Crohn’s disease but also in Serum tissue anti.transglutaminase antibodies in celiac disease36. It is then possible that specif- coeliac disease and other gastrointestinal dis- ic alimentary and/or bacterial may ease. Q J Med 2001; 94: 195-205. cause celiac disease in patients affected by 12) SBLATTERO D, BERTI I, TREVISIOL C, MARZARI R, TOMMASI- Crohn’s disease thanks to Th1 pathway. NI A, BRADBURY A, FASANO A, NOT T. Human recom- In conclusion, Crohn’s disease shows a binant ELISA: an innova- tive diagnostic assay for celiac disease. Am J strict correlation with celiac disease. This as- Gastroenterol 2000; 95: 1253-1257. sociation should kept in mind when we diag- nose a new case of Crohn’s disease. More ac- 13) FARRACE MG, PICARELLI A, DI TOLA M, SABBATELLA L, MARCHIONE OP, IPPOLITO G, PIACENTINI M. Presence of curate immunopathological studies should be anti-“tissue” transglutaminase antibodies in inflam- performed to explain whether there is a com- matory intestinal diseases: an apoptosis-associat- mon immunopathogenesis in both diseases. ed event? Cell Death Differ 2001; 8: 767-770.

129 A. Tursi, G.M. Giorgetti, G. Brandimarte, W. Elisei

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