Skip to main content

Advertisement

SpringerLink
Log in

Celiac disease poses significant risk in developing depression, anxiety, headache, epilepsy, panic disorder, dysthymia: A meta-analysis

  • Review Article
  • Published:
Indian Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Celiac disease (CD) primarily affects the small intestine. Previous studies have identified higher incidences of neuropsychiatric diseases among CD patients compared to non-CD controls. Genome-wide association studies have identified >60 non-human leukocyte antigen (HLA) genes associated with CD, where estimated 15% genes have role in neurological health. We carried out a systematic review and meta-analysis to estimate the potential risk conferred by CD in developing neuropsychiatric diseases. Literature search was performed till June 2019. Incidences of neuropsychiatric diseases were compared among CD and non-CD controls. Funnel plots and Egger’s tests were used to evaluate publication bias and estimate study effects. Qualities of the included studies were estimated using Newcastle-Ottawa Scale. Quality of evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Odds of developing neuropsychiatric diseases among CD were evaluated by computing meta-odds ratio (Manten-Haenszel method) and Z test p-value using random and fixed effect models based on the degree of study heterogeneity. Thirteen non-randomized case-control studies were found eligible. Subjects suffering from CD were found to have significantly more risk to develop depression (p<1.00E-05; OR=1.60 [1.37–1.86]), anxiety (p=0.05; OR=1.41 [1.00–1.97]), headache (p<0.1.00E-05; OR=3.27 [2.46–4.34]), epilepsy (p<1.00E-04; OR=11.90 [3.78–37.43]), panic disorder (p<1.00E-04; OR=4.64 [2.22–9.70]), and dysthymia (p=2.00E-03; OR=5.27 [1.83–15.22]). CD is a major predisposing factor in developing array of common neuropsychiatric diseases. Shared biological processes and molecular networks could play a crucial role in disease co-occurrence. Detailed molecular evidences are needed to establish the cause-effect relationship between these diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Code availability

NA

References

  1. Mooney PD, Hadjivassiliou M, Sanders DS. Coeliac disease. BMJ. 2014;348:g1561.

    Article  PubMed  Google Scholar 

  2. Lebwohl B, Ludvigsson JF, Green PH. Celiac disease and non-celiac gluten sensitivity. BMJ. 2015;351:h4347.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ludvigsson JF, Card T, Ciclitira PJ, et al. Support for patients with celiac disease: a literature review. United European Gastroenterol J. 2015;3:146–59.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Caio G, Volta U, Sapone A, et al. Celiac disease: a comprehensive current review. BMC Med. 2019;17:1–20.

    Article  CAS  Google Scholar 

  5. Lerner A. New therapeutic strategies for celiac disease. Autoimmun Rev. 2010;9:144–7.

    Article  CAS  PubMed  Google Scholar 

  6. Trynka G, Wijmenga C, Van Heel DA. A genetic perspective on coeliac disease. Trends Mol Med. 2010;16:537–50.

    Article  CAS  PubMed  Google Scholar 

  7. Malalgoda M, Simsek S. Celiac disease and cereal proteins. Food Hydrocoll. 2017;68:108–13.

    Article  CAS  Google Scholar 

  8. Rashtak S, Snyder MR, Pittock SJ, et al. Serology of celiac disease in gluten-sensitive ataxia or neuropathy: role of deamidated gliadin antibody. J Neuroimmunol. 2011;230:130–4.

    Article  CAS  PubMed  Google Scholar 

  9. Cooke WT, Smith WT. Neurological disorders associated with adult coeliac disease. Brain. 1966;89:683–722.

    Article  CAS  PubMed  Google Scholar 

  10. Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GA, Gibson A, Grünewald RA, Lobo AJ. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry. 1997;63:770–5.

  11. Briani C, Zara G, Alaedini A, et al. Neurological complications of celiac disease and autoimmune mechanisms: a prospective study. J Neuroimmunol. 2008;195:171–5.

    Article  CAS  PubMed  Google Scholar 

  12. Dohan FC. Hypothesis: Genes and neuroactive peptides from food as cause of schizophrenia. Adv Biochem Psychopharmacol. 1980;22:535–48.

    CAS  PubMed  Google Scholar 

  13. Pan Y, Cai W, Cheng Q, et al. Association between anxiety and hypertension: a systematic review and meta-analysis of epidemiological studies. Neuropsychiatr Dis Treat. 2015;11:1121–30.

    PubMed  PubMed Central  Google Scholar 

  14. Smith DF, Gerdes LU. Meta-analysis on anxiety and depression in adult celiac disease. Acta Psychiatr Scand. 2012;125:189–93.

    Article  CAS  PubMed  Google Scholar 

  15. LinZ Si Q, Xiaoyi Z. Association between epilepsy and systemic autoimmune diseases: a meta-analysis. Seizure. 2016;41:160–6.

    Article  Google Scholar 

  16. Senapati S, Sood A, Midha V, et al. Shared and unique common genetic determinants between pediatric and adult celiac disease. BMC Med Genet. 2016;9:44.

    Google Scholar 

  17. Senapati S, Gutierrez-Achury J, Sood A, et al. Evaluation of European coeliac disease risk variants in a north Indian population. Eur J Hum Genet. 2015;23:530–5.

    Article  CAS  PubMed  Google Scholar 

  18. Ferreira MA, O'Donovan MC, Meng YA, et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008;40:1056–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Athanasiu L, Mattingsdal M, Kähler AK, et al. Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort. J Psychiatry Res. 2010;44:748–53.

    Article  Google Scholar 

  20. The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43:969–76.

    Article  Google Scholar 

  21. Xie T, Deng L, Mei P, et al. A genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations. Neurobiol Aging. 2014;35:1778.e9–e23.

  22. Yang B, Curran BM, Tymanskyj SR. A Role for AnkyrinG in maturation and maintenance of the nodes of Ranvier. J Neurosci. 2017;37:5796–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–9.

    Article  PubMed  Google Scholar 

  24. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.

    Article  CAS  PubMed  Google Scholar 

  25. Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002.

    Article  PubMed  Google Scholar 

  26. Sandberg F, Viktorsdóttir MB, Salö M, et al. Comparison of major complications in children after laparoscopy-assisted gastrostomy and percutaneous endoscopic gastrostomy placement: a meta-analysis. Pediatr Surg Int. 2018;34:1321–7.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:401–6.

    Article  PubMed  Google Scholar 

  28. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  29. Addolorato G, Di Giuda D, De Rossi G, et al. Regional cerebral hypoperfusion in patients with celiac disease. Am J Med. 2004;116:312–7.

    Article  PubMed  Google Scholar 

  30. Zelnik N, Pacht A, Obeid R, Lerner A. Range of neurologic disorders in patients with celiac disease. Pediatrics. 2004;113:1672–6.

    Article  PubMed  Google Scholar 

  31. Lionetti E, Francavilla R, Maiuri L, et al. Headache in pediatric patients with celiac disease and its prevalence as a diagnostic clue. J Pediatr Gastroenterol Nutr. 2009;49:202–7.

    Article  PubMed  Google Scholar 

  32. Dimitrova AK, Ungaro RC, Lebwohl B, et al. Prevalence of migraine in patients with celiac disease and inflammatory bowel disease. J Headache Pain. 2013;53:344–55.

    Article  Google Scholar 

  33. Işıkay S, Kocamaz H, Sezer S, et al. The frequency of epileptiform discharges in celiac disease. Paediatr Neurol. 2015;53:78–82.

    Article  Google Scholar 

  34. Carta MG, Conti A, Lecca F, et al. The burden of depressive and bipolar disorders in celiac disease. Clin Pract Epidemiol Ment Health. 2015;11:180–5.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lebwohl B, Roy A, Alaedini A, et al. Risk of headache-related healthcare visits in patients with celiac disease: a population-based observational study. J Headache Pain. 2016;56:849–58.

    Article  Google Scholar 

  36. Garud S, Leffler D, Dennis M, et al. Interaction between psychiatric and autoimmune disorders in coeliac disease patients in the Northeastern United States. Aliment Pharmacol Ther. 2009;29:898–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Carta MG, Hardoy MC, Boi MF, et al. Association between panic disorder, major depressive disorder and celiac disease: a possible role of thyroid autoimmunity. J Psychosom Res. 2002;53:789–93.

    Article  PubMed  Google Scholar 

  38. Cicarelli G, Della Rocca G, Amboni M, et al. Clinical and neurological abnormalities in adult celiac disease. Neurol Sci. 2003;24:311–7.

    Article  CAS  PubMed  Google Scholar 

  39. Pynnönen PA, Isometsä ET, Aronen ET, et al. Mental disorders in adolescents with celiac disease. Psychosomatics. 2004;45:325–35.

    Article  PubMed  Google Scholar 

  40. Ludvigsson JF, Reutfors J, Ösby U, et al. Coeliac disease and risk of mood disorders—a general population-based cohort study. J Affect Disord. 2007;99:117–26.

    Article  PubMed  Google Scholar 

  41. West J, Logan RF, Hubbard RB, Card TR. Risk of schizophrenia in people with coeliac disease, ulcerative colitis and Crohn’s disease: a general population-based study. Aliment Pharmacol Ther. 2006;23:71–4.

    Article  CAS  PubMed  Google Scholar 

  42. Trovato CM, Raucci U, Valitutti, et al. Neuropsychiatric manifestations in celiac disease. Epilepsy Behav. 2019;99:106393.

    Article  PubMed  Google Scholar 

  43. Volta U, Giorgio RD, Petrolini N, et al. Clinical findings and anti-neuronal antibodies in coeliac disease with neurological disorders. Scand J Gastroenterol. 2002;37:1276–81.

    Article  CAS  PubMed  Google Scholar 

  44. Briani C, Zara G, Toffanin E, et al. Neurological complications of celiac disease and autoimmune mechanisms: preliminary data of a prospective study in adult patients. Ann N Y Acad Sci. 2005;1051:148–55.

    Article  CAS  PubMed  Google Scholar 

  45. Volta U, De Giorgio R, Granito A, et al. Anti-ganglioside antibodies in coeliac disease with neurological disorders. Dig Liver Dis. 2006;38:183–7.

    Article  CAS  PubMed  Google Scholar 

  46. Mata S, Renzi D, Pinto F, Calabro A. Anti-tissue transglutaminase IgA antibodies in peripheral neuropathy and motor neuronopathy. Acta Neurol Scand. 2006;114:54–8.

    Article  CAS  PubMed  Google Scholar 

  47. Işıkay S, Kocamaz H. Prevalence of celiac disease in children with idiopathic epilepsy in southeast Turkey. Pediatr Neurol. 2014;50:479–81.

    Article  PubMed  Google Scholar 

  48. Inaloo S, Dehghani SM, Farzadi F, et al. A comparative study of celiac disease in children with migraine headache and a normal control group. Turk J Gastroenterol. 2011;22:32–5.

    Article  PubMed  Google Scholar 

  49. Alehan F, Ozçay F, Eroi I, et al. Increased risk for coeliac disease in paediatric patients with migraine. Cephalalgia. 2008;28:945–9.

    Article  CAS  PubMed  Google Scholar 

  50. Antigoni M, Xinias I, Theodouli P, et al. Increased prevalence of silent celiac disease among Greek epileptic children. Pediatr Neurol. 2007;36:165–9.

    Article  PubMed  Google Scholar 

  51. Dalggiç B, Dursun I, Serdaroglu A, Dursun A. Latent and potential celiac disease in epileptic Turkish children. J Child Neurol. 2006;21:6–7.

    Article  Google Scholar 

  52. Gabrielli M, Cremonini F, Fiore G, et al. Association between migraine and celiac disease: results from a preliminary case-control and therapeutic study. Am J Gastroenterol. 2003;98:625–9.

    Article  PubMed  Google Scholar 

  53. Lahat E, Broide E, Leshem M, et al. Prevalence of celiac antibodies in children with neurologic disorders. Pediatr Neurol. 2000;22:393–6.

    Article  CAS  PubMed  Google Scholar 

  54. Pratesi R, Gandolfi L, Martins RC, et al. Is the prevalence of celiac disease increased among epileptic patients? Arq Neuropsiquiatr. 2003;61:330–4.

    Article  PubMed  Google Scholar 

  55. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev. 2014;94:355–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hays MT. Thyroid hormone and the gut. Endocr Res. 1988;14:203–24.

    Article  CAS  PubMed  Google Scholar 

  57. Di Liegro I. Thyroid hormones and the central nervous system of mammals. Mol Med Rep. 2008;1:279–95.

    PubMed  Google Scholar 

  58. Timiras PS, Nzekwe EU. Thyroid hormones and nervous system development. Neonatology. 1989;55:376–85.

    Article  CAS  Google Scholar 

  59. Pratesi R, Gandolfi L, Friedman H, et al. Serum IgA antibodies from patients with coeliac disease react strongly with human brain blood-vessel structures. Scand J Gastroenterol. 1998;33:817–21.

    Article  CAS  PubMed  Google Scholar 

  60. Ricaño-Ponce I, Wijmenga C, Gutierrez-Achury J. Genetics of celiac disease. Best Pract Res Clin Gastroenterol. 2015;29:399–412.

    Article  PubMed  Google Scholar 

  61. Krishnareddy S. The microbiome in celiac disease. Gastroenterol Clin N Am. 2019;48:115–26.

    Article  Google Scholar 

  62. Valles-Colomer M, Falony G, Darzi Y, et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nat Microbiol. 2019;4:623–32.

    Article  CAS  PubMed  Google Scholar 

  63. Liang S, Wu X, Hu X, et al. Recognizing depression from the microbiota–gut–brain axis. Int J Mol Sci. 2018;19:1592.

    Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge financial supports from DST-SERB (#ECR/2016/001660), UGC-BSR grant (30-4/2014-BSR) to SS. KS is supported by Fogarty International Centre, National Institute of Health (NIH), United States (Grant award: 1K43TW011164). NS is supported by DST-WOS-A Fellowship (Grant award: SR/WOS-A/LS-333/2018).  

Author information

Authors and Affiliations

  1. Immunogenomics Laboratory, Department of Human Genetics and Molecular Medicine, School of Life Sciences, Central University of Punjab, Bathinda, 151 401, India

    Nidhi Sharma & Sabyasachi Senapati

  2. Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurugram, 122 002, India

    Kavita Singh

  3. Centre for Chronic Disease Control, New Delhi, 110 016, India

    Kavita Singh

  4. Rollins School of Public Health, Emory University, Atlanta, USA

    Kavita Singh

Authors
  1. Nidhi Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kavita Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sabyasachi Senapati
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SS and NS conceptualized and designed the study. NS performed the systematic review and performed the meta-analysis. SS and KS checked and reviewed the analysis. NS and SS wrote the manuscript. All the authors reviewed and approved the final draft of the manuscript.

Corresponding author

Correspondence to Sabyasachi Senapati.

Ethics declarations

Ethics approval

NA

Consent to participate

NA

Consent for publication

The corresponding author is submitting on behalf of the research group.

Conflict of interest

NS, KS, and SS declare no competing interests.

Disclaimer

The authors are solely responsible for the data and the contents of the paper. In no way, the Honorary Editor-in-Chief, Editorial Board Members, the Indian Society of Gastroenterology or the printer/publishers are responsible for the results/findings and content of this article.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(XLSX 14 kb)

ESM 2

(XLSX 19 kb)

ESM 3

(DOCX 81 kb)

ESM 4

(DOC 63 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharma, N., Singh, K. & Senapati, S. Celiac disease poses significant risk in developing depression, anxiety, headache, epilepsy, panic disorder, dysthymia: A meta-analysis. Indian J Gastroenterol 40, 453–462 (2021). https://doi.org/10.1007/s12664-021-01215-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12664-021-01215-2

Keywords

Search

Navigation