Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease

Norelle R Reilly, Benjamin Lebwohl, Rolf Hultcrantz, Peter H R Green, Jonas F Ludvigsson, Norelle R Reilly, Benjamin Lebwohl, Rolf Hultcrantz, Peter H R Green, Jonas F Ludvigsson

Abstract

Background & aims: Non-alcoholic fatty liver disease is a common cause of chronic liver disease. Celiac disease alters intestinal permeability and treatment with a gluten-free diet often causes weight gain, but so far there are few reports of non-alcoholic fatty liver disease in patients with celiac disease.

Methods: Population-based cohort study. We compared the risk of non-alcoholic fatty liver disease diagnosed from 1997 to 2009 in individuals with celiac disease (n = 26,816) to matched reference individuals (n = 130,051). Patients with any liver disease prior to celiac disease were excluded, as were individuals with a lifetime diagnosis of alcohol-related disorder to minimize misclassification of non-alcoholic fatty liver disease. Cox regression estimated hazard ratios for non-alcoholic fatty liver disease were determined.

Results: During 246,559 person-years of follow-up, 53 individuals with celiac disease had a diagnosis of non-alcoholic fatty liver disease (21/100,000 person-years). In comparison, we identified 85 reference individuals diagnosed with non-alcoholic fatty liver disease during 1,488,413 person-years (6/100,000 person-years). This corresponded to a hazard ratio of 2.8 (95% CI 2.0-3.8), with the highest risk estimates seen in children (HR = 4.6; 95% CI 2.3-9.1). The risk increase in the first year after celiac disease diagnosis was 13.3 (95% CI 3.5-50.3) but remained significantly elevated even beyond 15 years after the diagnosis of celiac disease (HR = 2.5; 95% CI 1.0-5.9).

Conclusion: Individuals with celiac disease are at increased risk of non-alcoholic fatty liver disease compared to the general population. Excess risks were highest in the first year after celiac disease diagnosis, but persisted through 15 years after diagnosis with celiac disease.

Keywords: Autoimmune; Celiac disease; Gluten; NAFLD; NASH; Steatohepatitis.

Conflict of interest statement

Conflict of Interest: None.

Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Figures

Log-minus-log curve examining proportional hazards
Log-minus-log curve examining proportional hazards

References

    1. Rubio-Tapia A, Murray JA. The liver in celiac disease. Hepatology. 2007;46:1650–1658.
    1. Ludvigsson JF, Elfstrom P, Broome U, Ekbom A, Montgomery SM. Celiac disease and risk of liver disease: a general population-based study. Clin Gastroenterol Hepatol. 2007;5:63–69. e61.
    1. Barshop NJ, Sirlin CB, Schwimmer JB, Lavine JE. Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;28:13–24.
    1. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–285.
    1. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80.
    1. Abenavoli L, Milic N, De Lorenzo A, Luzza F. A pathogenetic link between nonalcoholic fatty liver disease and celiac disease. Endocrine. 2013;43:65–67.
    1. Patton HM, Yates K, Unalp-Arida A, Behling CA, Huang TT, Rosenthal P, et al. Association between metabolic syndrome and liver histology among children with nonalcoholic Fatty liver disease. Am J Gastroenterol. 2010;105:2093–2102.
    1. Margariti A, Deutsch M, Manolakopoulos S, Tiniakos D, Papatheodoridis GV. The severity of histologic liver lesions is independent of body mass index in patients with nonalcoholic fatty liver disease. J Clin Gastroenterol. 2013;47:280–286.
    1. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129.
    1. Bhat G, Baba CS, Pandey A, Kumari N, Choudhuri G. Life style modification improves insulin resistance and liver histology in patients with non-alcoholic fatty liver disease. World J Hepatol. 2012;4:209–217.
    1. Reilly NR, Aguilar K, Hassid BG, Cheng J, Defelice AR, Kazlow P, et al. Celiac disease in normal-weight and overweight children: clinical features and growth outcomes following a gluten-free diet. J Pediatr Gastroenterol Nutr. 2011;53:528–531.
    1. Cheng J, Brar PS, Lee AR, Green PH. Body mass index in celiac disease: beneficial effect of a gluten-free diet. J Clin Gastroenterol. 2010;44:267–271.
    1. Norsa L, Shamir R, Zevit N, Verduci E, Hartman C, Ghisleni D, et al. Cardiovascular disease risk factor profiles in children with celiac disease on gluten-free diets. World J Gastroenterol. 2013;19:5658–5664.
    1. Peters U, Askling J, Gridley G, Ekbom A, Linet M. Causes of death in patients with celiac disease in a population-based Swedish cohort. Arch Intern Med. 2003;163:1566–1572.
    1. Volynets V, Kuper MA, Strahl S, Maier IB, Spruss A, Wagnerberger S, et al. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD) Dig Dis Sci. 2012;57:1932–1941.
    1. Alisi A, Manco M, Devito R, Piemonte F, Nobili V. Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2010;50:645–649.
    1. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877–1887.
    1. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. 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.
    1. Heyman M, Abed J, Lebreton C, Cerf-Bensussan N. Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis. Gut. 2012;61:1355–1364.
    1. Rubio-Tapia A, Barton SH, Rosenblatt JE, Murray JA. Prevalence of small intestine bacterial overgrowth diagnosed by quantitative culture of intestinal aspirate in celiac disease. J Clin Gastroenterol. 2009;43:157–161.
    1. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–845.
    1. Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, Ekbom A. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol. 2009;24:659–667.
    1. Ludvigsson JF, Brandt L, Montgomery SM. Symptoms and signs in individuals with serology positive for celiac disease but normal mucosa. BMC Gastroenterol. 2009;9:57.
    1. Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F. Small-intestinal histopathology and mortality risk in celiac disease. JAMA. 2009;302:1171–1178.
    1. Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450.
    1. Olen O, Bihagen E, Rasmussen F, Ludvigsson JF. Socioeconomic position and education in patients with coeliac disease. Dig Liver Dis. 2012;44:471–476.
    1. Ludvigsson JF, Brandt L, Montgomery SM, Granath F, Ekbom A. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol. 2009;9:19.
    1. Itoh S, Yougel T, Kawagoe K. Comparison between nonalcoholic steatohepatitis and alcoholic hepatitis. Am J Gastroenterol. 1987;82:650–654.
    1. Rahimi AR, Daryani NE, Ghofrani H, Taher M, Pashaei MR, Abdollahzade S, et al. The prevalence of celiac disease among patients with non-alcoholic fatty liver disease in Iran. Turk J Gastroenterol. 2011;22:300–304.
    1. Bardella MT, Valenti L, Pagliari C, Peracchi M, Fare M, Fracanzani AL, et al. Searching for coeliac disease in patients with non-alcoholic fatty liver disease. Dig Liver Dis. 2004;36:333–336.
    1. Kabbani TA, Kelly CP, Betensky RA, Hansen J, Pallav K, Villafuerte-Galvez JA, et al. Patients with celiac disease have a lower prevalence of non-insulin-dependent diabetes mellitus and metabolic syndrome. Gastroenterology. 2013;144:912–917. e911.
    1. Kalsch J, Bechmann LP, Manka P, Kahraman A, Schlattjan M, Marth T, et al. Non-alcoholic steatohepatitis occurs in celiac disease and is associated with cellular stress. Z Gastroenterol. 2013;51:26–31.
    1. van Elburg RM, Uil JJ, Mulder CJ, Heymans HS. Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut. 1993;34:354–357.
    1. Giorgio V, Miele L, Principessa L, Ferretti F, Villa MP, Negro V, et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis. 2014
    1. Riordan SM, McIver CJ, Thomas DH, Duncombe VM, Bolin TD, Thomas MC. Luminal bacteria and small-intestinal permeability. Scand J Gastroenterol. 1997;32:556–563.
    1. Mohler KM, Sleath PR, Fitzner JN, Cerretti DP, Alderson M, Kerwar SS, et al. Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature. 1994;370:218–220.
    1. Ludvigsson JF, Wahlstrom J, Grunewald J, Ekbom A, Montgomery SM. Coeliac disease and risk of tuberculosis: a population based cohort study. Thorax. 2007;62:23–28.
    1. Ludvigsson JF, Sanders DS, Maeurer M, Jonsson J, Grunewald J, Wahlstrom J. Risk of tuberculosis in a large sample of patients with coeliac disease--a nationwide cohort study. Aliment Pharmacol Ther. 2011;33:689–696.
    1. Ludvigsson JF, Brandt L, Montgomery SM, Granath F, Ekbom A. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers. BMC Gastroenterol. 2009;9:19.
    1. Carjsö KSB, Spetz CL. Evaluation of the Data quality in the Swedish National Hospital Discharge Register. Book Evaluation of the Data quality in the Swedish National Hospital Discharge Register. 1998:1–10. (Editor edˆeds) City: WHO/HST/ICD/C/98.34.
    1. Walker MM, Murray JA, Ronkainen J, Aro P, Storskrubb T, D'Amato M, et al. Detection of Celiac Disease and Lymphocytic Enteropathy by Parallel Serology and Histopathology in a Population-Based Study. Gastroenterology. 2010;139:112–119.
    1. Olen O, Montgomery SM, Marcus C, Ekbom A, Ludvigsson JF. Coeliac disease and body mass index: A study of two Swedish general population-based registers. Scand J Gastroenterol. 2009;44:1198–1206.
    1. Review T, LaBrecque DR, Abbas Z, Anania F, Ferenci P, Khan AG, et al. World Gastroenterology Organisation global guidelines: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin Gastroenterol. 2014;48:467–473.
    1. OECD. Health at a Glance: Europe 2012. Chapter 2.6.1. Alcohol consumption among population aged 15 years and over, 2010 and change, 1980-2010. 2012
    1. Brown I, Mino-Kenudson M, Deshpande V, Lauwers GY. Intraepithelial lymphocytosis in architecturally preserved proximal small intestinal mucosa: an increasing diagnostic problem with a wide differential diagnosis. Archives of pathology & laboratory medicine. 2006;130:1020–1025.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe