Abstract
Aims
Previous studies have reported conflicting results regarding prevalence of elevated LC (2–70%) in celiac disease (CD). This systematic review and meta-analysis assessed the prevalence of elevated LC at time of CD diagnosis and associated response to GFD. We also report the prevalence of CD in patients with unexplained elevation of LC.
Methods
Studies assessing LC (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) in CD patients were eligible. Studies with < 50 cases or in pediatric populations were excluded.
Results
In total, 20 studies assessing prevalence of elevated LC in 4,265 participants with newly diagnosed CD (mean age = 35.6 ± 6.5 years, 69.8% female) were included. Pooled prevalence of elevated LC was 18.7% (95% CI 13.8–24.8; I2 = 95%). Normalization of elevated LC was seen in 83.1% (95% CI 73.4–89.7; I2 = 79%, 11 studies) of patients after GFD. On meta-regression, age at CD diagnosis, gender, and Marsh grading were not associated with elevated LC.
Among 979 participants (7 studies) with unexplained elevation of LC, pooled seroprevalence and biopsy-proven CD was 6.4% (95% CI 2.9–10.3, I2 = 71%) and 4.5% (95% CI 2.6–7.7, I2 = 67%), respectively.
Conclusion
Elevated LC are seen in approximately one-fifth of patients at CD diagnosis with majority normalizing after GFD. Age, gender, and degree of intestinal damage are not predictive of elevated LC. In the appropriate clinical scenario, liver tests should be serially monitored in CD reserving workup for additional causes after a trial of GFD. Patients with unexplained elevation of liver tests should be screened for celiac disease.
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Data availability
The data that support the findings of this study are available from the corresponding author, [ART], upon reasonable request.
Abbreviations
- AILD:
-
Autoimmune liver disease
- BMI:
-
Body mass index
- CD:
-
Celiac disease
- DGP:
-
Deamidated gliadin
- EMA:
-
Endomysial antibodies
- GFD:
-
Gluten-free diet
- HLA:
-
Human leucocyte antigen
- LC:
-
Liver chemistries
- NAFLD:
-
Non-alcoholic fatty liver disease
- TTG:
-
Tissue transglutaminase
References
Lebwohl B, Rubio-Tapia A. Epidemiology, Presentation, and Diagnosis of Celiac Disease. Gastroenterology 2021;160:63–75.
Leffler DA, Green PHR, Fasano A. Extraintestinal manifestations of coeliac disease. Nat Rev Gastroenterol Hepatol 2015;12:561–571.
Rubio-Tapia A, Murray JA. The Liver and Celiac Disease. Clin Liver Dis 2019;23:167–176.
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.
Jericho H, Sansotta N, Guandalini S. Extraintestinal Manifestations of Celiac Disease: Effectiveness of the Gluten-Free Diet. J Pediatr Gastroenterol Nutr 2017;65:75–79.
Iwańczak B, Mowszet K, Waszczuk E et al. Clinical differences of celiac disease in schoolchildren and adults. Adv Clin Exp Med 2009;18:153–158.
Villavicencio Kim J, Wu GY. Celiac disease and elevated liver enzymes: A review. J Clin Transl Hepatol 2021;9:116–124.
Rubio-Tapia A, Murray JA. Liver involvement in celiac disease. Minerva Med 2008;99:595–604.
Korpimäki S, Kaukinen K, Collin P et al. Gluten-sensitive hypertransaminasemia in celiac disease: An infrequent and often subclinical finding. Am J Gastroenterol 2011;106:1689–1696.
Zanini B, Baschè R, Ferraresi A et al. Factors that contribute to hypertransaminasemia in patients with celiac disease or functional gastrointestinal syndromes. Clin Gastroenterol Hepatol 2014;12:804-810.e2.
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.
Iacono O Lo, Petta S, Venezia G, et al. Anti-tissue transglutaminase antibodies in patients with abnormal liver tests: Is it always coeliac disease? Am J Gastroenterol 2005;100:2472–2477.
Ghozzi M, Ben Salem MA, Mbarki F et al. Screening for celiac disease, by endomysial antibodies, in patients with unexplained hypertransaminasaemia. Scand J Clin Lab Invest 2017;77:454–457.
Sainsbury A, Sanders DS, Ford AC. Meta-analysis: Coeliac disease and hypertransaminasaemia. Aliment Pharmacol Ther 2011;34:33–40.
Moher D, Liberati A, Tetzlaff J et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med 2009;151:264–269.
Stroup DF, Berlin JA, Morton SC et al. Meta-analysis of observational studies in epidemiology: A proposal for reporting. J Am Med Assoc 2000;283:2008–2012.
Rubio-Tapia A, Hill ID, Kelly CP et al. ACG clinical guidelines: Diagnosis and management of celiac disease. Am J Gastroenterol 2013;108:656–676.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603–605.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188.
Kanwal F, White D. “Systematic Reviews and Meta-analyses” in Clinical Gastroenterology and Hepatology. Clin Gastroenterol Hepatol 2012;10:1184–1186.
Higgins JPT, Thompson SG, Deeks JJ et al. Measuring inconsistency in meta-analyses. Br Med J 2003;327:557–560.
Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7. Rating the quality of evidence - Inconsistency. J Clin Epidemiol 2011;64:1294–1302.
Mohan BP, Adler DG. Heterogeneity in systematic review and meta-analysis: how to read between the numbers. Gastrointest Endosc 2019;89:902–903.
Easterbrook PJ, Gopalan R, Berlin JA et al. Publication bias in clinical research. Lancet 1991;337:867–872.
Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56:455–463.
Castillo NE, Vanga RR, Theethira TG et al. Prevalence of abnormal liver function tests in celiac disease and the effect of a gluten-free diet in the US Population. Am J Gastroenterol 2015;110:1216–1222.
Dickey W, McMillan SA, Collins JSA et al. Liver abnormalities associated with celiac sprue: How common are they, what is their significance, and what do we do about them? J Clin Gastroenterol 1995;20:290–292.
Ehsani-Ardakani MJ, Nejad MR, Villanacci V et al. Gastrointestinal and non-gastrointestinal presentation in patients with celiac disease. Arch Iran Med 2013;16:78–82.
Fernández A, González L, de-la-Fuente J. Coeliac disease: Clinical features in adult populations. Rev Esp Enfermedades Dig 2010;102:466–471.
Masood N, Shaikh IA. Clinical presentations and biochemical profile in adult celiac disease patients in Hyderabad: Pakistan. Pakistan J Med Sci 2014;30:287–290.
Moghaddam MA, Nejad MR, Shalmani HM et al. The effects of gluten-free diet on hypertransaminasemia in patients with celiac disease. Int J Prev Med 2013;4:700–704.
Nijhawan S, Katiyar P, Nagaich N et al. Prevalence of associated disorders in Indian patients with celiac disease. Indian J Gastroenterol 2013;32:330–334.
Novacek G, Miehsler W, Wrba F et al. Prevalence and clinical importance of hypertransaminasaemia in coeliac disease. Eur J Gastroenterol Hepatol 1999;11:283–288.
Rispo A, Imperatore N, Guarino M et al. Metabolic-associated fatty liver disease (MAFLD) in coeliac disease. Liver Int 2021;41:788–798.
Sharma M, Singh P, Agnihotri A et al. Celiac disease: A disease with varied manifestations in adults and adolescents. J Dig Dis 2013;14:518–525.
Vivas S, Ruiz De Morales JM, Fernandez M, et al. Age-related clinical, serological, and histopathological features of celiac disease. Am J Gastroenterol 2008;103:2360–2365.
Shahbazkhani B, Mehrabi G, Nasiritosi M et al. Celiac disease in cryptogenic hypertransaminasemia. Tehran Univ Med J 2010;68:428–433.
Múgica F, Castiella A, Otazua P et al. Prevalence of coeliac disease in unexplained chronic hypertransaminasemia. Rev Esp Enfermedades Dig 2001;93:711–714.
Volta U, Granito A, De Franceschi L et al. Anti tissue transglutaminase antibodies as predictors of silent coeliac disease in patients with hypertransaminasaemia of unknown origin. Dig Liver Dis 2001;33:420–425.
Soresi M, Amplo M, Agliastro R et al. Screening for autoantibodies to tissue transglutaminase reveals a low prevalence of celiac disease in blood donors with cryptogenic hypertransaminasemia. Digestion 2001;64:87–91.
Bardella MT, Vecchi M, Conte D et al. Chronic unexplained hypertransaminasemia may be caused by occult celiac disease. Hepatology 1999;29:654–657.
Abbas Z, Raza S, Yakoob J et al. Varied presentation of celiac disease in pakistani adults. J Coll Physicians Surg Pakistan 2013;23:522–524.
Binicier OB, Tosun F. Evaluation of adult celiac disease from a tertiary reference center: A retrospective analysis. Rev Assoc Med Bras 2020;66:55–60.
Casella G, Antonelli E, Di Bella C et al. Prevalence and causes of abnormal liver function in patients with coeliac disease. Liver Int 2013;33:1128–1131.
Lauret E, Rodrigo L. Celiac disease and autoimmune-associated conditions. Biomed Res Int 2013;2013:1–17.
Jacobsen MB, Fausa O, Elgjo K et al. Hepatic lesions in adult coeliac disease. Scand J Gastroenterol 1990;25:656–662.
Ludvigsson JF, Elfström P, BroomÉ U et al. Celiac Disease and Risk of Liver Disease: A General Population-Based Study. Clin Gastroenterol Hepatol 2007;5:63-69.e1.
Panetta F, Nobili V, Sartorelli MR et al. Celiac disease in pediatric patients with autoimmune hepatitis: Etiology, diagnosis, and management. Pediatr Drugs 2012;14:35–41.
Tortora R, Capone P, De Stefano G et al. Metabolic syndrome in patients with coeliac disease on a gluten-free diet. Aliment Pharmacol Ther 2015;41:352–359.
Imperatore N, Tortora R, Testa A et al. Proton pump inhibitors as risk factor for metabolic syndrome and hepatic steatosis in coeliac disease patients on gluten-free diet. J Gastroenterol 2018;53:507–516.
Younossi ZM, Koenig AB, Abdelatif D et al. Global epidemiology of nonalcoholic fatty liver disease—Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.
Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol 2017;112:18–35.
Pedreira S, Sugai E, Moreno ML et al. Significance of smooth muscle/anti-actin autoantibodies in celiac disease. Acta Gastroenterol Latinoam 2005;35:83–93.
Dutta R, Iqbal A, Das P et al. Liver involvement in patients with coeliac disease: Proof of causality using IgA/anti-TG2 colocalisation techniques. J Clin Pathol 2021;74:766–773.
Korponay-Szabó IR, Halttunen T, Szalai Z et al. In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut 2004;53:641–648.
Elli L, Bergamini CM, Bardella MT et al. Transglutaminases in inflammation and fibrosis of the gastrointestinal tract and the liver. Dig Liver Dis 2009;41:541–550.
Hoffmanová I, Sánchez D, Tučková L et al. Celiac disease and liver disorders: From putative pathogenesis to clinical implications. Nutrients 2018;10:892.
Rubio-Tapia A, Ludvigsson JF, Brantner TL et al. The prevalence of celiac disease in the United States. Am J Gastroenterol 2012;107:1538–1544.
Acknowledgments
We would like to thank Mary Schleicher (Medical Librarian) at Floyd Loop Alumni Library, Cleveland Clinic for help with literature search.
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Conceptualization and Methodology: MA, RG, CJK, ART. Data Curation and Formal Analysis: MA, RJ, PK. Interpretation of data: MA, RG, CCL, JWF, CJK, ART. Drafting of Manuscript: MA, RG, CJK. Review, Editing and Final Approval: All authors.
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Aggarwal, M., Garg, R., Kumar, P. et al. Bi-directional Relationship Between Celiac Disease and Liver Chemistries: A Systematic Review and Meta-Analysis. Dig Dis Sci 68, 1369–1380 (2023). https://doi.org/10.1007/s10620-022-07663-w
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DOI: https://doi.org/10.1007/s10620-022-07663-w