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It’s curious to think there was a time when the words “gluten” and “celiac disease” weren’t part of the common vernacular. Until a few decades ago, celiac was considered to be an uncommon disease affecting mainly children and limited to individuals of European ancestry.¹ However, rates of celiac disease have grown to the point where it is now considered a major public health problem worldwide.¹ In fact, a 2020 meta-analysis shows the incidence of celiac disease has increased an average of 7.5% per year over the past several decades, with incidence highest in females and children.² The pooled global prevalence of celiac disease has been reported at 1.4% based on serologic tests, with prevalence values at 0.4% in South America, 0.5% in Africa and North America, 0.6% in Asia, and 0.8% in Europe and Oceania.¹

Furthermore, the prevalence of undiagnosed celiac disease showed a dramatic increase in the US in the early 21^st century,³ with an estimate 80% of people with celiac disease undiagnosed in 2009.⁴ According to findings from the National Health and Nutrition Examination surveys from 2009 to 2014, the prevalence of undiagnosed celiac disease remained substantial, but decreased to less than 50% in 2013 and 2014.^4,5

In the following video, renowned celiac researcher Alessio Fasano, MD, speaks with IFM Educator and Senior Advisor to the CEO Patrick Hanaway, MD, on how research has impacted estimated prevalence rates of celiac disease in the US.

Celiac is not the only autoimmune condition increasing in prevalence—so, too, is type 1 diabetes.⁶ Interestingly, between 10% and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5% to 7% of patients with autoimmune thyroid disease and/or type 1 diabetes are IgA anti-tissue transglutaminase antibody positive.⁷ And while the close relationship between celiac disease and endocrine autoimmunity is largely explained by sharing a common genetic background,⁷ researchers speculate that the cause of the rise of celiac disease is likely environmental and linked to gluten intolerance.⁸

Manifestations & the Triad

In celiac disease, gluten has been established as the instigator of autoimmunity; the classical presentation consists of gastrointestinal symptoms associated with malabsorption, including diarrhea, steatorrhea, weight loss, or failure to thrive.⁸ Extra-intestinal symptoms include iron deficiency, aphthous stomatitis, chronic fatigue, short stature, reduced bone density, and neurological symptoms.⁹ A 2020 meta-analysis also found that compared to healthy controls, patients with celiac disease showed a significant increased risk for developing certain psychological or neurodevelopmental disorders such as autistic spectrum disorder, attention deficit hyperactivity disorder, depression, anxiety, and eating disorders.¹⁰

The cause of the disease is an interaction among a triad of factors: genetic susceptibility due in part to HLA haplotype, environmental factors, and intestinal permeability.^11,12 More recently, researchers have found that HLA haplotype may impact the make-up of the intestinal microbiome, creating an environment in which dysbiosis can lead to loss of immune tolerance to gluten.¹³ There is speculation that environmental factors such as breastfeeding may be protective, perhaps by influencing the gut microbiome.¹³

Treatment & Mortality Risk

The main treatment for celiac disease is a strict, lifelong adherence to a gluten-free diet.⁸ The autoimmune process is halted by removing gluten from the diet, which allows for resolution of celiac autoimmune enteropathy and subsequent normalization of serological markers of the disease.⁸ Yet alarmingly, recent research suggests that some “gluten-free” foods sold in the US actually contain trace levels of the substance that contribute to symptoms and persistent intestinal histologic damage.^14,15 Research is ongoing into alternative treatments for celiac disease that may not require a zero-gluten diet,^4,9 such as the use of probiotics to improve gastrointestinal symptoms¹⁶ and the use of gluten-degrading enzymes.¹⁷

While an association between diagnosed celiac disease and increased mortality has been documented, mortality risk associated with undiagnosed celiac disease remains uncertain, with conflicting study results.⁴ A 2009 study of 9,133 healthy young adults at Warren Air Force Base found, during 45 years of follow-up, that undiagnosed celiac disease was associated with a nearly four-fold increased risk of death.³ Other studies with much shorter time frames, including a 2009 cohort study (n=6,987) with up to 28 years of follow-up¹⁸ and a 2017 community-based study (n=30,425) with a six-year follow-up,¹⁹ did not find a significant association between disease status and survival rate. It should be noted that the mentioned studies all used serological analysis (tests for tissue transglutaminase and endomysial antibodies) to define the undiagnosed celiac disease study populations subsequently used for mortality risk analysis.^3,18,19

At IFM’s Immune Advanced Practice Module, expert functional medicine clinicians will present the latest research on celiac disease and non-celiac gluten sensitivity and provide you with the tools for identifying these conditions and treating them effectively.

Related Articles

Fasano’s Triad and the Trajectory of Autoimmunity

Innovations in the Treatment of Autoimmune Diseases

Non-Celiac Immune Responses to Gluten

References

1. Singh P, Arora A, Strand TA, et al. Global prevalence of celiac disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-836.e2. doi:10.1016/j.cgh.2017.06.037
2. King JA, Jeong J, Underwood FE, et al. Incidence of celiac disease is increasing over time: a systematic review and meta-analysis. Am J Gastroenterol. 2020;115(4):507-525. doi:10.14309/ajg.0000000000000523
3. Rubio-Tapia A, Kyle RA, Kaplan EL, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology. 2009;137(1):88-93. doi:10.1053/j.gastro.2009.03.059
4. Lebwohl B, Sanders DS, Green PHR. Coeliac disease. Lancet. 2018;391(10115):70-81. doi:10.1016/S0140-6736(17)31796-8
5. Choung RS, Unalp-Arida A, Ruhl CE, Brantner TL, Everhart JE, Murray JA. Less hidden celiac disease but increased gluten avoidance without a diagnosis in the United States: findings from the National Health and Nutrition Examination Surveys from 2009 to 2014. Mayo Clin Proc. 2016;S0025-6196(16)30634-6. doi:10.1016/j.mayocp.2016.10.012
6. Centers for Disease Control and Prevention. Rates of new diagnosed cases of type 1 and type 2 diabetes continue to rise among children, teens. Updated February 11, 2020. Accessed January 4, 2021. https://www.cdc.gov/diabetes/research/reports/children-diabetes-rates-rise.html
7. Kahaly GJ, Frommer L, Schuppan D. Celiac disease and endocrine autoimmunity – the genetic link. Autoimmun Rev. 2018;17(12):1169-1175. doi:10.1016/j.autrev.2018.05.013
8. Serena G, Camhi S, Sturgeon C, Yan S, Fasano A. The role of gluten in celiac disease and type 1 diabetes. Nutrients. 2015;7(9):7143-7162. doi:10.3390/nu7095329
9. Caio G, Volta U, Sapone A, et al. Celiac disease: a comprehensive current review. BMC Med. 2019;17(1):142. doi:10.1186/s12916-019-1380-z
10. Clappison E, Hadjivassiliou M, Zis P. Psychiatric manifestations of coeliac disease, a systematic review and meta-analysis. Nutrients. 2020;12(1):142. doi:10.3390/nu12010142
11. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev.2011;91(1):151-175. doi:10.1152/physrev.00003.2008
12. Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci.2012;1258(1):25-33. doi:10.1111/j.1749-6632.2012.06538.x
13. Serena G, Lima R, Fasano A. Genetic and environmental contributors for celiac disease. Curr Allergy Asthma Rep. 2019;19(9):40. doi:10.1007/s11882-019-0871-5
14. Syage JA, Kelly CP, Dickason MA, et al. Determination of gluten consumption in celiac disease patients on a gluten-free diet. Am J Clin Nutr. 2018;107(2):201-207. doi:10.1093/ajcn/nqx049
15. Falcomer AL, Santos Araújo L, Farage P, Santos Monteiro J, Yoshio Nakano E, Puppin Zandonadi R. Gluten contamination in food services and industry: a systematic review. Crit Rev Food Sci Nutr. 2020;60(3):479-493. doi:10.1080/10408398.2018.1541864
16. Seiler CL, Kiflen M, Stefanolo JP, et al. Probiotics for celiac disease: a systematic review and meta-analysis of randomized controlled trials. Am J Gastroenterol. 2020;115(10):1584-1595. doi:10.14309/ajg.0000000000000749
17. Olshan KL, Leonard MM, Serena G, Zomorrodi AR, Fasano A. Gut microbiota in celiac disease: microbes, metabolites, pathways and therapeutics. Expert Rev Clin Immunol. Published online December 27, 2020. doi:10.1080/1744666X.2021.1840354
18. Lohi S, Mäki M, Rissanen H, Knekt P, Reunanen A, Kaukinen K. Prognosis of unrecognized coeliac disease as regards mortality: a population-based cohort study. Ann Med. 2009;41(7):508-515. doi:10.1080/07853890903036199
19. Choung RS, Larson SA, Khaleghi S, et al. Prevalence and morbidity of undiagnosed celiac disease from a community-based study. Gastroenterology. 2017;152(4):830-839.e5. doi:10.1053/j.gastro.2016.11.043