Dr. Robert Pastore, PhD, CNS

Celiac Disease: High Risk Groups, Related Disorders and Comorbidities

Published on September 12, 2019
READ TIME: 10 minutes

As I discuss in my article Celiac Disease: A Clinical Chameleon, celiac disease can be vexing in how it presents in clinical practice. In this article, my goal is to cover current conditions and diseases that have been linked to celiac disease in multiple studies in peer-reviewed literature. Take a moment to review the list below.1

Diseases & Conditions Linked to Celiac Disease
Addison disease
Atrial fibrillation
Autoimmune hepatitis
Autoimmune thyroiditis
Budd Chiari syndrome
Cancers - gliomas, breast, lung, lymphomas, ovarian, pancreatic
Cardiovascular disease
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Epilepsy
Immune thrombocytopenia purpura
Juvenile idiopathic arthritis
Microscopic colitis
Multiple Sclerosis
Nonalcoholic fatty liver disease
Primary biliary cirrhosis
Rheumatoid Arthritis
Sarcoidosis
Sjogren’s syndrome
Systemic lupus erythematosus
Thromboembolic disease
Turner syndrome
Type 1 Diabetes
Williams syndrome

While the above list is not exhaustive, it is a representation of the most common associated conditions and if you or a loved one are experiencing one of the aforementioned, please draw their attention to my article What do you do if you think you may have celiac disease? and hopefully start the diagnostic process. Let’s briefly examine a pathway between celiac disease and other diseases, particularly autoimmune diseases.

Zonulin, Intestinal Barrier Function Immunology and Comorbidities

The equilibrium between tolerance and immunity to non-self-antigens is dependent upon the tight junctions of the intestinal epithelial barrier, which, like a conductor, directs the orchestra of the gut-associated lymphoid tissue and the neuroendocrine network of the intestines.3 A physiological modulator that regulates the tolerance and immune response balance by controlling the flux of macromolecules across the intestinal barrier is the protein zonulin.3

Fasano discovered that small intestine exposure to gliadin is a powerful trigger of zonulin release.3 While Drago and colleagues noted zonulin release by enteric bacterial infection of the small intestine, gliadin remains the most powerful zonulin stimulant. 4 Lammers and colleagues have shown that the chemokine receptor CXCR3, which is overexpressed in celiac disease patients, co-localizes with gliadin, recruiting the adaptor protein MyD88, resulting in the release of zonulin and subsequent increase in intestinal permeability.5 This is critical information as numerous diseases are recognized to involve alterations in intestinal permeability due to impaired tight junctions of the small intestine.58

In various autoimmune diseases such as multiple sclerosis, type 1 diabetes and rheumatoid arthritis, what is shared with celiac disease is a breach of the tight junctions of the small intestine that allows antigens to pass through the intestinal lumen, provoking an immune system response that can then target any organ, tissue or gland.9 Zonulin is over expressed in tissues of individuals with autoimmune diseases.3 Fasano and colleagues have shown that within minutes of gliadin exposure, human intestinal cells secrete large amounts of zonulin.3 Moreover, this breaching of the intestinal tight junction of the small intestine allows gliadin to translocate to the lamina propria, triggering the proinflammatory interleukin 15 (IL-15) and interleukin 8 (IL-8) as well as keratinocyte growth factor.11 While this is transpiring, the Toll like receptor 4-MD2-CD14 complex results in the presence of proinflammatory cytokines.11 Continued immune system response mechanisms ensue.

Rodrigo and colleagues noted an increased prevalence of celiac disease in multiple sclerosis patients suggesting a rate of gluten intolerance 11 times higher than the general population.12 Mormile agrees with Rodrigo and recommends celiac disease patients be evaluated for multiple sclerosis and vice versa.13 Mormile states that celiac disease and multiple sclerosis may share osteopontin gene splice variants, acting as inducers toward a multiple sclerosis diagnosis in celiac disease patients.13 Fasano has linked various neurological diseases such as multiple sclerosis to zonulin release in celiac disease patients.3

Asleh and colleagues have associated gliadin and the stimulation of zonulin to type 1 diabetes autoimmunity in human studies.14 Yachyshyn and colleagues discovered an increase in serum zonulin in multiple sclerosis patients.15 Celiac disease and the autoimmune thyroid diseases Grave’s disease, Hashimoto’s thyroiditis and idiopathic myxedema, share the DQ2 allele, which explains why there is a higher incidence of such endocrinopathies in celiac disease.16 Celiac disease has also been implicated in hypo and hyper primary and secondary parathyroidism.17 Heneghan and colleagues have found a 100-fold increase in Addison’s disease among celiac disease patients and suggest that Addison’s disease patients should be screened for celiac disease.19 The suspected connection is via the HLA-DQ8 allele.19

Zhernakova and colleagues have established a shared genetic basis between rheumatoid arthritis and celiac disease, with an overrepresentation of T-cell signaling.20 Fourteen loci were identified that are shared between celiac disease and rheumatoid arthritis, indicating an overlapping genetic basis for both diseases and implicating altered T-cell activation and differentiation as a similar stimulating matter of autoimmunity.20

Using an autoimmune comorbidity model, we can see how consumption of gluten in the celiac patient can lead to a compromise of the intestinal tight junctions via zonulin release, with continued hyperpermeability from the presence of zonulin occludens toxin, resulting in circulating immune complexes, creating a secondary autoimmune presentation.32224 If the celiac patient falls into the obese category, inflammasome activation continues this autoimmune cascade.26 Using pathology as an example, a celiac disease patient may present with a diagnosis of rheumatoid arthritis, multiple sclerosis, type 1 diabetes, ankylosing spondylitis, or another disease due to the circulating autoimmune complexes that may infiltrate through the intestinal lumen.32128 This creates a different viewpoint of the diagnosis of celiac disease. Individuals with celiac disease should be tested for the aforementioned diseases and vice versa.20


  1. 1. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol 2013; 108:656–676; doi:10.1038/ajg.2013.79.

  2. 2. Bai JC, Ciacci C, Corazza GR, Fried M, Olano C, Rostami-Nejad M., Gonzalez A, Green P, Gutierrez-Achury J, Schultz M, Verdu E, Barada K, Gibson P, Koletzko S, Coton T, Mulder C, Makharia G, LeMair A. World Gastroenterology Organisation Global Guidelines. Celiac Disease. July 2016. Available from http://www.worldgastroenterology.org/guidelines/global-guidelines/celiac-disease/celiac-disease-english on July 15, 2017.

  3. 3. Fasano A. Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer. Physiol Rev. 2011;91:151–175.

  4. 4. Drago S, Asmar REL, DI Pierro M, Clemente-Grazia M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D’Agate, C, Not Tarcisio, Zampini L, Catassi C, Fasano A. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006:41:408-419.

  5. 5. Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN,Fasano A. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterol. 2008;135:194–204.

  6. 6. Sapone A, Lammers KM, Vincenzo C, Cammarota M, Giuliano MT. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011;23:1741-7015.

  7. 7. Latif S, Jamal A, Memon I, Yasmeen S, Tresa V, Shaikh S. Multiple autoimmune syndrome: Hashimoto's thyroiditis, celiac disease and systemic lupus erythematosus. J Pak Med Assoc. 2010;60:863-865.

  8. 8. Rodrigo L, Hernández-Lahoz C, Fuentes D, Alvarez N, López-Vázquez A, González S. Prevalence of celiac disease in multiple sclerosis. BMC Neurol. 2011;31:1-7.

  9. 9. Abreu MT. Toll-like receptor signaling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol. 2010;10:131–144.

  10. 10. Sonier B, Patrick C, Ajjikuttira P, Scott FW. Intestinal immune regulation as a potential diet-modifiable feature of gut inflammation and autoimmunity. Int Rev Immunol. 2009;28:414-445.

  11. 11. Caio G, Volta U, Sapone A, Leffler DA, De Giorgio R, Catassi C, Fasano A. Celiac disease: a comprehensive current review. BMC Med. 2019 Jul 23;17(1):142. doi: 10.1186/s12916-019-1380-z. Review. PubMed PMID: 31331324; PubMed Central PMCID: PMC6647104.

  12. 12. Rodrigo L, Hernández-Lahoz C, Fuentes D, Alvarez N, López-Vázquez A, González S. Prevalence of celiac disease in multiple sclerosis. BMC Neurol. 2011;31:1-7.

  13. 13. Mormile R. Multiple sclerosis and susceptibility to celiac disease: An osteopontin gene haplotypes affair? Immunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.11.015

  14. 14. Asleh R, Marsh S, Shilkrut M, Binah O, Guetta J, Lejbkowicz F, Enav B, Shehadeh N, Kanter Y, Lache O, Cohen O, Levy NS, Levy AP. Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ Res. 2003;92: 1193–1200.

  15. 15. Yacyshyn B, Meddings J, Sadowski D, Bowen-Yacyshyn MB. Multiple sclerosis patients have peripheral blood CD45RO B cells and increased intestinal permeability. Dig Dis Sci. 1996;41:2493.

  16. 16. Kumar V, Rajadhyaksha M, Wortsman J. Celiac disease-associated autoimmune endocrinopathies. Clin Diag Lab Immunol. 2001;8:678-685.

  17. 17. Kumar V, Rajadhyaksha M, Wortsman J. Celiac disease-associated autoimmune endocrinopathies. Clin Diag Lab Immunol. 2001;8:678-685.

  18. 18. Silvester JA, Rashid M. Long-term follow-up of individuals with celiac disease: an evaluation of current practice guidelines. Can J Gastroenterol. 2007;9:557-564.

  19. 19. Heneghan, MA, McHugh P, Stevens, FM, McCarthy CF. Addison’s disease and selective IgA deficiency in two celiac patients. Scand. J. Gastroenterol. 1997;32:509–511.

  20. 20. Zhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. . PLOS Genetics. 2011;7:1-13.

  21. 21. Lindfors K, Koskinen O, Kaukinen, K. An update on the diagnostics of celiac disease. Int Rev Immunol. 2011;30:185-196.

  22. 22. Freeman HJ, Chopra A, Clandinin MT, Thomson A. Recent advances in celiac disease. World J Gastroenterol. 2011;17: 2259-2272.

  23. 23. Drago S, Asmar REL, DI Pierro M, Clemente-Grazia M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D’Agate, C, Not Tarcisio, Zampini L, Catassi C, Fasano A. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006:41:408-419.

  24. 24. Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterol. 2008;135:194–204.

  25. 25. Latif S, Jamal A, Memon I, Yasmeen S, Tresa V, Shaikh S. Multiple autoimmune syndrome: Hashimoto's thyroiditis, celiac disease and systemic lupus erythematosus. J Pak Med Assoc. 2010;60:863-865.

  26. 26. Lukens, JR, Dixit, VD, Kanneganti TD. Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. Discov Med. 2011;12:65-74.

  27. 27. Green PH, Cellier C. Celiac Disease. N Engl J Med. 2007;357:1731-1743.

  28. 28. Sapone A, Lammers KM, Vincenzo C, Cammarota M, Giuliano MT. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 2011;23:1741-7015.