Abstract
Celiac disease (CD) is defined as a permanent intolerance to ingested wheat gliadins and other cereal prolamins, occurring in genetically susceptible people. Persistent elevation of serum aminotransferase activity is expression of liver damage related to CD, which occurs in two distinctive forms. The most frequent is a mild asymptomatic liver injury, with a moderate increase of serum aminotransferase activities and a mild inflammatory portal and lobular infiltrate on liver biopsy (celiac hepatitis), reversible on a gluten-free diet (GFD). More rarely, severe and progressive inflammatory liver damage, induced by an autoimmune process and identified as autoimmune hepatitis (AIH), can develop and it is generally unaffected by gluten withdrawal.
Surveys that included only pediatric patients report a wide range of prevalence of CD in AIH of 11.5–46% (mean 21.5%). CD and AIH share selected combinations of genes coding for class II human leukocyte antigens, which could explain their coexistence. Increased intestinal permeability and circulation of anti-tissue transglutaminase (tTG) have also been considered as further potential causes of liver damage in CD patients. tTG in the liver and in other extraintestinal tissues could modify other external- or self-antigens and generate different neo-antigens, which are responsible for liver injury in patients with CD.
Patients with AIH represent a population at high risk for developing CD; screening for CD should be integrated into the diagnostic routine of all patients with AIH, with or without gastrointestinal manifestations, before starting immunosuppressive treatments. The only currently available treatment for CD is the GFD and the supportive nutritional care for iron, calcium, and vitamin deficiencies. Due to the difficulties of a GFD, in the past decade researchers have become increasingly interested in therapeutic alternatives to continuous or intermittent use of a GFD in patients with CD. Interventions addressed to correct the defect in the intestinal barrier are currently at the most advanced stage of clinical trials. The impact of a GFD on the outcome of AIH is not clear but it seems to be ineffective in the treatment of AIH. The early detection and treatment of CD, however, may prevent progression to end-stage liver failure.
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References
Alaedini A, Green PHR. Narrative review: celiac disease: understanding a complex autoimmune disorder. Ann Int Med 2005; 142: 289–98
Hill ID, Dirks MH, Liptak GS, et al., North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005 Jan; 40(1): 1–19
Fasano A, Araya M, Bhatnagar S, et al. Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition consensus report on celiac disease. Celiac Disease Working Group, FISPGHAN. J Pediatr Gastroenterol Nutr 2008 Aug; 47(2): 214–9
Pollock DJ. The liver in coeliac disease. Histopathology 1977; 1: 421–30
Bardella MT, Fraquelli M, Quatrini M, et al. Prevalence of hypertransaminasemia in adult coeliac patients and effect of gluten-free diet. Hepatology 1995; 22: 833–6
Davison S. Coeliac disease and liver dysfunction. Arch Dis Child 2002; 87: 293–6
Duggan JM, Duggan AE. Systematic review: the liver in coeliac disease. Aliment PharmacoI Ther 2005; 21: 515–8
Maggiore G, Caprai S. The liver in celiac disease. J Pediatr Gastroenterol Nutr 2003; 37: 117–9
Maggiore G, Caprai S. Liver involvement in celiac disease. Indian J Pediatr 2006; 73: 809–11
Jacobsen MB, Fausa O, Elgjo K, et al. Hepatic lesions in adult coeliac disease. Scand J Gastroenterol 1990; 25: 656–62
Di Sabatino A, Corazza GR. Coeliac disease. Lancet 2009; 373: 1480–93
Sorensen HT, Thulstrup AM, Blomqvist P, et al. Risk of primary biliary liver cirrhosis in patients with coeliac disease: Danish and Swedish cohort data. Gut 1999; 44: 736–8
Lawson A, West J, Aithal GP, et al. Autoimmune cholestatic liver disease in people with coeliac disease: a population-based study of their association. Aliment Pharmacol Ther 2005; 21: 401–5
Villalta D, Girolami D, Bidoli E, et al. High prevalence of celiac disease in autoimmune hepatitis detected by anti-tissue transglutaminase autoantibodies. J Clin Lab Anal 2005; 19(1): 6–10
Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a 20-year experience. Hepatology 1997; 25: 541–7
Mirzaagha F, Azali SH, Islami F, et al. Coeliac disease in autoimmune liver disease: a cross-sectional study and a systematic review. Dig Liver Dis 2010 Sep; 42(9): 620–3
Rewers M. Epidemiology of celiac disease: what are the prevalence, incidence, and progression of celiac disease? Gastroenterology 2005 Apr; 128(4 Suppl. 1): S47–51
Dubé C, Rostom A, Sy R, et al. The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review. Gastroenterology 2005 Apr; 128(4 Suppl. 1): S57–67
Caprai S, Vajro P, Ventura A, et al. Autoimmune liver disease associated with celiac disease in childhood: a multicenter study. SIGENP Study Group for Autoimmune Liver Disorders in Celiac Disease. Clin Gastroenterol Hepatol 2008 Jul; 6(7): 803–6
Diamanti A, Basso MS, Pietrobattista A, et al. Prevalence of celiac disease in children with autoimmune hepatitis [letter]. Dig Liver Dis 2008 Dec; 40(12): 965
Tosun MS, Ertekin V, Selimoğlu MA. Autoimmune hepatitis associated with celiac disease in childhood. Eur J Gastroenterol Hepatol 2010 Jul; 22(7): 898–9
El-Shabrawi M, El-Karaksy H, Mohsen N, et al. Celiac disease in children and adolescents with autoimmune hepatitis: a single-centre experience. J Trop Pediatr 2011 Apr; 57(2): 104–8
Beuers U, Rust C. Overlap syndromes. Semin Liver Dis 2005; 25: 311–20
Zawahir S, Safta A, Fasano A. Pediatric celiac disease. Curr Opin Pediatr 2009 Oct; 21(5): 655–60
Clemente MG, De Virgiliis S, Kang JS, et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut 2003 Feb; 52(2): 218–23
Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997 Jul; 3(7): 797–801
Periolo N, Chernavsky AC. Celiac disease. Autoimmun Rev 2006; 5: 202–8
Cantarero Vallejo MD, Gómez Camarero J, Menchén L, et al. Liver damage and celiac disease. Rev Esp Enferm Dig 2007 Nov; 99(11): 648–52
Viljamaa M, Kaukinen K, Huhtala H, et al. Coeliac disease, autoimmune diseases and gluten exposure. Scand J Gastroenterol 2005 Apr; 40(4): 437–43
Tollefsen S, Arentz-Hansen H, Fleckenstein B, et al. HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J Clin Invest 2006 Aug; 116(8): 2226–36
Czaja AJ, Donaldson PT. Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis. Immunol Rev 2000; 174: 250–9
Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006; 354: 54–66
Smyth C, Kelleher D, Keeling PWN. Hepatic manifestations of gastrointestinal diseases: inflammatory bowel disease, celiac disease, and Whipple’s disease. Clin Liver Dis 2002; 6: 1013–2
Ventura A, Magazzù G, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. SIGEP Study Group for Autoimmune Disorders in Celiac Disease. Gastroenterology 1999; 117: 297–303
Sategna Guidetti C, Solerio E, Scaglione N, et al. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders. Gut 2001 Oct; 49(4): 502–5
Volta U, Granito A, De Franceschi L, et al. Anti tissue transglutaminase antibodies as predictors of silent celiac disease in patients with hypertransaminasemia of unknown origin. Dig Liver Dis 2001; 33: 420–5
Pelaez-Luna M, Schmulson M, Robles-Diaz G. Intestinal involvement is not sufficient to explain hypertransaminasemia in celiac disease? Med Hypotheses 2005; 65: 937–41
Korponay-Szabó IR, Halttunen T, Szalai Z, et al. In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut 2004 May; 53(5): 641–8
Binder HJ. Disorders of absorption. In: Fauci AS, Braunwald E, Kasper DL, et al., editors. Harrison’s principles of internal medicine. New York: McGraw-Hill Medical, 2008: 1872–86
O’Mahony S, Howdle PD, Losowsky MS. Management of patients with non-responsive coeliac disease. Aliment Pharmacol Ther 1996 Oct; 10(5): 671–80
Rubio-Tapia A, Abdulkarim AS, Wiesner RH, et al. Celiac disease autoantibodies in severe autoimmune liver disease and the effect of liver transplantation. Liver Int 2008 Apr; 28(4): 467–76
Craig D, Robins G, Howdle PD. Advances in CD. Curr Opin Gastroenterol 2007; 23: 142–8
Leffler DA, Schuppan D. Update on serologic testing in celiac disease. Am J Gastroenterol 2010 Dec; 105(12): 2520–4
Kaukinen K, Partanen J, Mäki M, et al. HLA-DQ typing in the diagnosis of celiac disease. Am J Gastroenterol 2002 Mar; 97(3): 695–9
Marsh MN, Crowe PT. Morphology of the mucosal lesion in gluten sensitivity. Baillieres Clin Gastroenterol 1995; 9: 273–93
Hopman EG, le Cessie S, von Blomberg BM, et al. Nutritional management of the gluten-free diet in young people with celiac disease in The Netherlands. J Pediatr Gastroenterol Nutr 2006 Jul; 43(1): 102–8
Leonardi S, Pavone P, Rotolo N, et al. Autoimmune hepatitis associated with celiac disease in childhood: report of two cases. J Gastroenterol Hepatol 2003 Nov; 18(11): 1324–7
Dickey W, McMillan SA, Callender ME. High prevalence of coeliac sprue among patients with primary biliary cirrhosis. J Clin Gastroenterol 1997; 25: 328–9
Volta U, Rodrigo L, Granito A, et al. Celiac disease in autoimmune cholestatic liver disorders. Am J Gastroenterol 2002 Oct; 97(10): 2609–13
Kaukinen K, Halme L, Collin P, et al. Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology 2002 Apr; 122(4): 881–8
Habior A, Lewartowska A, Orłowska J, et al. Association of coeliac disease with primary biliary cirrhosis in Poland. Eur J Gastroenterol Hepatol 2003 Feb; 15(2): 159–64
Lerner A. New therapeutic strategies for celiac disease. Autoimmun Rev 2010 Jan; 9(3): 144–7
Paterson BM, Lammers KM, Arrieta MC, et al. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther 2007; 26:757–66
Molberg O, Uhlen AK, Jensen T, et al. Mapping of gluten T-cell epitopes in the bread wheat ancestors: implications for celiac disease. Gastroenterology 2005; 128: 393–401
Pinier M, Verdu EF, Nasser-Eddine M, et al. Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium. Gastroenterology 2009 Jan; 136(1): 288–98
Silano M, Di Benedetto R, Trecca A, et al. A decapeptide from durum wheat prevents celiac peripheral blood lymphocytes from activation by gliadin peptides. Pediatr Res 2007; 61: 67–71
Silano M, Leonardi F, Trecca A, et al. Prevention by a decapeptide from durum wheat of in vitro gliadin peptide-induced apoptosis in small-bowel mucosa from coeliac patients. Scand J Gastroenterol 2007; 42: 786–7
Matysiak-Budnik T, Candalh C, Cellier C, et al. Limited efficiency of prolyl-endopeptidase in the detoxification of gliadin peptides in celiac disease. Gastroenterology 2005; 129: 786–96
Gianfrani C, Siciliano RA, Facchiano AM, et al. Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease. Gastroenterology 2007; 133: 780–9
Gass J, Khosla C. Prolyl endopeptidases. Cell Mol Life Sci 2007; 64: 345–55
Gass J, Bethune MT, Siegel M, et al. Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue. Gastroenterology 2007; 133: 472–80
Di Cagno R, de Angelis M, Alfonsi G, et al. Pasta made from durum wheat semolina fermented with selected lactobacilli as a tool for a potential decrease of the gluten intolerance. J Agric Food Chem 2005; 53: 4393–402
De Angelis M, Rizzello CG, Fasano A, et al. VSL#3 probiotic preparation has the capacity to hydrolyze gliadin polypeptides responsible for Celiac Sprue. Biochim Biophys Acta 2006; 1762: 80–93
Gobbetti M, Giuseppe Rizzello C, Di Cagno R, et al. Sourdough lactobacilli and celiac disease. Food Microbiol 2007 Apr; 24: 187–96
Di Cagno R, Rizzello CG, De Angelis M, et al. Use of selected sourdough strains of Lactobacillus for removing gluten and enhancing the nutritional properties of gluten-free bread. J Food Prot 2008; 71: 1491–5
Di Cagno R, De Angelis M, Auricchio S, et al. Sourdough bread made from wheat and nontoxic flours and started with selected lactobacilli is tolerated in celiac sprue patients. Appl Environ Microbiol 2004; 70: 1088–96
Esposito C, Caputo I, Troncone R. New therapeutic strategies for coeliac disease: tissue transglutaminase as a target. Curr Med Chem 2007; 14: 2572–80
Choi K, Siegel M, Piper JL, et al. Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2. Chem Biol 2005; 12: 469–75
Anderson RP, van Heel DA, Tye-Din JA, et al. Antagonists and nontoxic variants of the dominant wheat gliadin T cell epitope in coeliac disease. Gut 2006; 55: 485–91
Silano M, Vincentini O, Iapello A, et al. Antagonist peptides of the gliadin T-cell stimulatory sequences: a therapeutic strategy for celiac disease. J Clin Gastroenterol 2008; 42 (Suppl. 3 Pt 2): S191–2
Fraser JS, Engel W, Ellis HJ, et al. Coeliac disease: in vivo toxicity of the putative immunodominant epitope. Gut 2003; 52: 1698–02
Silano M, Di Benedetto R, Maialetti F, et al. A 10-residue peptide from durum wheat promotes a shift from a Th1-type response toward a Th2-type response in celiac disease. Am J Clin Nutr 2008; 87: 415–23
Salvati VM, Mazzarella G, Gianfrani C, et al. Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa. Gut 2005; 54: 46–53
Anderson RP, Degano P, Godkin AJ, et al. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med 2000; 6: 337–42
Gianfrani C, Levings MK, Sartirana C, et al. Gliadin specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells. J Immunol 2006; 177: 4178–86
Senger S, Luongo D, Maurano F, et al. Intranasal administration of a re-combinant alpha-gliadin down-regulates the immune response to wheat gliadin in DQ8 transgenic mice. Immunol Lett 2003; 88: 127–34
Sollid LM, Khosla C. Future therapeutic options for celiac disease. Nat Clin Pract Gastroenterol Hepatol 2005; 2: 140–7
Zhao J, de Vera J, Narushima S, et al. R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice. Gastroenterology 2007; 132: 1331–43
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Panetta, F., Nobili, V., Sartorelli, M.R. et al. Celiac Disease in Pediatric Patients with Autoimmune Hepatitis. Pediatr Drugs 14, 35–41 (2012). https://doi.org/10.2165/11593150-000000000-00000
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DOI: https://doi.org/10.2165/11593150-000000000-00000