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DOI: 10.1055/s-0032-1330421
Non-Alcoholic Steatohepatitis Occurs in Celiac Disease and is Associated with Cellular Stress
Fettleber bei Sprue: eine Rolle für zellulären Stress?Publikationsverlauf
09. November 2012
03. Dezember 2012
Publikationsdatum:
11. Januar 2013 (online)
![](https://www.thieme-connect.de/media/zfg/201301/lookinside/thumbnails/10.1055-s-0032-1330421-1.jpg)
Abstract
Background and Aims: Liver and gut not only share alimentary but also immunological features. Major histocompatibility complex class I-related chains A and B (MIC A/B) function as indicators for cellular stress. These so called stress-induced ligands are suggested to play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) and are a prominent feature of celiac disease (CD).
Patients and Methods: In the present study, 24 patients with celiac disease and 20 patients with non-alcoholic steatohepatitis (NASH) were included. Liver enzymes, serum cell death markers (M30, M65), MIC B and expression of adiponectin were determined.
Results: Mean patient age was 42 years (18 − 69) for CD and 49 years (33 − 68) for the NASH group. ALT and AST values were lower in CD compared to NASH patients. While serum cell death markers were higher in NASH, the predominant type of cell death in CD was apoptosis. Also, expression of MIC B was significantly up-regulated in CD patients as compared to NASH patients. Adiponectin values were significantly lower in NASH compared to CD patients.
Conclusion: Stress-induced ligands and apoptosis are induced in CD. Prospective studies need to determine the exact role of cellular stress and apoptosis in the gut-liver axis and the clinical implications to screen for NAFLD in CD patients.
Zusammenfassung
Hintergrund: Leber und Darm weisen simultane alimentäre und immunologische Funktionen auf. Die Histokompatibilitätskomplex-Klasse I Kette A und B (MIC A/B) fungieren als Indikator für zellulären Stress. Es wird angenommen, dass diese sog. stressinduzierten Liganden, die ein bekanntes Charakteristikum der Zöliakie sind, auch eine wichtige Rolle in der Progression der nicht alkoholischen Fettlebererkrankung (NAFLD) spielen.
Methodik: In dieser Analyse wurden 24 Zöliakie-Patienten mit 20 Patienten einer nicht alkoholischen Steatohepatitis (NASH) hinsichtlich ihrer Leberenzyme, Zelltodmarkern (M30, M65), MIC B und der Expression von Adiponektin verglichen.
Ergebnisse: Das mittlere Alter der Zöliakie-Patienten betrug 42 Jahre (18 − 69), das der NASH-Patienten lag bei 49 Jahren (33 − 68). Patienten mit Zöliakie wiesen im Vergleich zu NASH-Patienten sowohl höhere Leberenzyme als auch vermehrte Apoptosemarker (Verhältnis Apoptose/Nekrose) auf. Gleichzeitig war die Expression von MIC B in Patienten mit Zöliakie im Vergleich zu NASH-Patienten signifikant erhöht. Patienten mit NASH hatten darüber hinaus signifikant niedrigere Adiponektin-Werte als Zöliakie-Patienten.
Schlussfolgerung: Stressinduzierte Liganden und Apoptose-induzierter Zelltod sind bei Patienten mit Zöliakie aktiviert. Weitere prospektive Studien, welche die Beziehung zwischen Leber und Darm näher untersuchen, sind notwendig, um zu klären, wann Zöliakie-Patienten für das Vorliegen einer NAFLD untersucht werden sollten.
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References
- 1 Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003; 98: 960-967
- 2 Browning JD, Szczepaniak LS, Dobbins R et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 1387-1395
- 3 Bechmann LP, Hannivoort RA, Gerken G et al. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol 2012; 56: 952-964
- 4 van der Poorten D, Samer C, Ramezani-Moghadam M et al. Hepatic fat loss in advanced nash: Are alterations in serum adiponectin the cause?. Hepatology 2012; [Epub ahead of print]
- 5 Wree A, Kahraman A, Gerken G et al. Obesity affects the liver – the link between adipocytes and hepatocytes. Digestion 2010; 83: 124-133
- 6 Henao-Mejia J, Elinav E, Jin C et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482: 179-185
- 7 Green PH, Cellier C. Celiac disease. N Engl J Med 2007; 357: 1731-1743
- 8 Pollock DJ. The liver in coeliac disease. Histopathology 1977; 1: 421-430
- 9 Rubio-Tapia A, Murray JA. The liver in celiac disease. Hepatology 2007; 46: 1650-1658
- 10 Miele L, Valenza V, La Torre G et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009; 49: 1877-1887
- 11 Abenavoli L, Milic N, De Lorenzo A et al. A pathogenetic link between non-alcoholic fatty liver disease and celiac disease. Endocrine 2012; [Epub ahead of print]
- 12 Kahraman A, Schlattjan M, Kocabayoglu P et al. Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis. Hepatology 2010; 51: 92-102
- 13 Chen Y, Cheng M, Tian Z. Hepatitis B virus down-regulates expressions of MHC class I molecules on hepatoplastoma cell line. Cell Mol Immunol 2006; 3: 373-378
- 14 Jinushi M, Takehara T, Tatsumi T et al. Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas. J Hepatol 2005; 43: 1013-1020
- 15 Kohga K, Takehara T, Tatsumi T et al. Serum levels of soluble major histocompatibility complex (MHC) class I-related chain A in patients with chronic liver diseases and changes during transcatheter arterial embolization for hepatocellular carcinoma. Cancer Sci 2008; 99: 1643-1649
- 16 Karacki PS, Gao X, Thio CL et al. MIC A and recovery from hepatitis C virus and hepatitis B virus infections. Genes Immun 2004; 5: 261-266
- 17 Meresse B, Chen Z, Ciszewski C et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 2004; 21: 357-366
- 18 Hue S, Mention JJ, Monteiro RC et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 2004; 21: 367-377
- 19 Kahraman A. Role of stress-iinduced NKG2D ligands in liver disease. Liver Int 2011; 1478-3223
- 20 Martin-Pagola A, Perez-Nanclares G, Ortiz L et al. MIC A response to gliadin in intestinal mucosa from celiac patients. Immunogenetics 2004; 56: 549-554
- 21 Husby S, Koletzko S, Korponay-Szabo IR et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012; 54: 136-160
- 22 Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 2001; 21: 3-16
- 23 Kleiner DE, Brunt EM, Van Natta M et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313-1321
- 24 Feldstein AE, Wieckowska A, Lopez AR et al. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009; 50: 1072-1078
- 25 Kalsch J, Bechmann LP, Kalsch H et al. Evaluation of Biomarkers of NAFLD in a Cohort of Morbidly Obese Patients. J Nutr Metab 2011; [Epub ahead of print]
- 26 Feldstein AE. Novel insights into the pathophysiology of nonalcoholic fatty liver disease. Semin Liver Dis 2010; 30: 391-401
- 27 Cheung O, Sanyal AJ. Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28: 351-359
- 28 Ertle J, Dechene A, Sowa JP et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011; 128: 2436-2443
- 29 Canbay A, Gieseler RK, Gores GJ et al. The relationship between apoptosis and non-alcoholic fatty liver disease: an evolutionary cornerstone turned pathogenic. Z Gastroenterol 2005; 43: 211-217
- 30 Green PH, Jabri B. Coeliac disease. Lancet 2003; 362: 383-391
- 31 Shan L, Molberg O, Parrot I et al. Structural basis for gluten intolerance in celiac sprue. Science 2002; 297: 2275-2279
- 32 Eade MN, Cooke WT, Williams JA. Liver disease in Crohn’s disease. A study of 100 consecutive patients. Scand J Gastroenterol 1971; 6: 199-204
- 33 Panaccione R, Sandborn WJ. Medical therapy of Crohn’s disease. Curr Opin Gastroenterol 2004; 20: 351-359
- 34 Tacke F, Weiskirchen R. Liver fibrosis – pathogenesis and novel therapeutic approaches. Internist 2010; 51: 21-29
- 35 Vajro P, Fontanella A, Mayer M et al. Elevated serum aminotransferase activity as an early manifestation of gluten-sensitive enteropathy. J Pediatr 1993; 122: 416-419
- 36 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; 122: 881-888
- 37 Abdo A, Meddings J, Swain M. Liver abnormalities in celiac disease. Clin Gastroenterol Hepatol 2004; 2: 107-112
- 38 Volta U. Liver dysfunction in celiac disease. Minerva Med 2008; 99: 619-629
- 39 Volta U. Pathogenesis and clinical significance of liver injury in celiac disease. Clin Rev Allergy Immunol 2009; 36: 62-70
- 40 Bardella MT, Fraquelli M, Quatrini M et al. Prevalence of hypertransaminasemia in adult celiac patients and effect of gluten-free diet. Hepatology 1995; 22: 833-836
- 41 Wigg AJ, Roberts-Thomson IC, Dymock RB et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001; 48: 206-211
- 42 Imajo K, Fujita K, Yoneda M et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab 2012; 16: 44-54
- 43 Mention JJ, Ben Ahmed M, Begue B et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 2003; 125: 730-745
- 44 Gao B. Natural killer group 2 member D, its ligands, and liver disease: good or bad?. Hepatology 2010; 51: 8-11
- 45 Germain RN, Margulies DH. The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol 1993; 11: 403-450
- 46 Bjorkman PJ, Parham P. Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem 1990; 59: 253-288
- 47 Nehra V, Angulo P, Buchman AL et al. Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis. Dig Dis Sci 2001; 46: 2347-2352
- 48 Lin HZ, Yang SQ, Chuckaree C et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000; 6: 998-1003
- 49 Feldstein AE, Werneburg NW, Canbay A et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 2004; 40: 185-194