Celiac disease (CD) is an immune reaction in the small bowel that is mediated by the ingestion of gluten and leads to a proinflammatory state that affects multiple organ systems.1,2 The underlying pathophysiology of CD is complex and includes both the immune system and gut microbiome.1 The prevalence of CD varies based on region of the world; however, the overall worldwide prevalence has been estimated to be approximately 1%.1 With the prevalence of CD in the United States steadily increasing over the past several decades, all medicine subspecialties have been caring for an increasing number of patients with CD.1
A frequent concern in the short-term and long-term management of CD is the potential risk for developing cancer, specifically within the small bowel. A study conducted by Askling et al found that adults with CD had an elevated overall risk for cancer with a standardized incidence ratio [SIR] of 1.3 that declined over time.3 Increased risk was found for lymphomas and small bowel, oropharyngeal, esophageal, colorectal, hepatobiliary, and pancreatic cancers. Small intestine (SIR 10), esophagus (SIR 4.2), lymphoma (SIR 5.9) Hodgkin lymphoma (SIR 4.6), and non-Hodgkin lymphoma (SIR 6.3) had the highest SIRs.
A study conducted by Elfström et al specifically evaluated the risk of gastrointestinal (GI) cancer in patients with CD.4 The authors found a higher incidence of GI cancers within the first year of diagnosis of CD with a hazard ratio (HR) between 5.95 and 9.13 depending on the degree of inflammation on biopsy. After the first year following diagnosis, the patients were found to have no statistically significant increase in risk of developing GI cancers. The absolute risk for any GI cancer was reported as 101 per 100,000 person-years.
Han et al conducted a meta-analysis that included 17 studies and identified a pooled odds ratio (OR) for risk of GI malignancy to be 1.60 (95% CI, 1.39-1.84).5 Esophageal (pooled OR 3.72) and small bowel carcinoma (OR 14.41) were the GI cancers found to be associated with significantly increased risk, although there was a high degree of heterogeneity between the studies assessed.
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Despite many studies showing a potential association between CD and small bowel cancer, there is a lack of data evaluating the risk of specific subtypes of small bowel cancer, such as lymphomas, adenocarcinomas, carcinoids, and sarcomas. Emilsson et al recently reviewed a large Swedish cohort that included 48,119 patients with CD who were followed for a median of 11 years.2 A total of 29 patients (0.06%) with CD were diagnosed with small bowel adenocarcinoma. Starting at 1 year after CD diagnosis, the following was found: the HR for small bowel adenocarcinoma was 3.05 (95% CI, 1.86-4.99), the HR for small bowel carcinoid tumor was 0.59 (95% CI, 0.16-2.10), and the HR for small bowel adenoma was 5.73 (95% CI, 3.70-8.88).
The HRs associated with small bowel adenocarcinoma correspond to 1 extra case of SB adenocarcinoma for every 2944 patients with CD followed for 10 years. The HR was highest during the first 10 years of follow-up; however, there was no difference by age or sex. The HR of small bowel adenocarcinoma was higher for those located in the jejunum and ileum (HR 3.92; 95% CI, 1.80-8.56) compared with those located in the duodenum (HR 2.69; 95% CI, 1.46-4.96). The risk of small bowel adenoma was highest during the first 2 years after a diagnosis of CD and then after more than 15 years of follow-up. No statistically significant difference was identified between mucosal healing and risk of small bowel adenocarcinoma (HR 0.18; 95% CI, 0.02-1.61) or small bowel adenomas (HR 0.79; 95% CI, 0.26-2.36).
The study authors noted that their HRs and the overall risk of small bowel adenocarcinoma of 0.06% were lower compared with prior studies. Although there was an increased risk compared with the general population, the study authors did not recommend routine screening based on the low absolute risk. Despite the lack of statistical significance between mucosal healing and small bowel adenocarcinoma risk, the study authors still believe that improved healing may lead to decreased risk of small bowel cancer over time. It is important to note that this study only included patients with CD from Sweden and therefore may not be representative of patients seen in the United States.
This study raises several interesting points. Despite the lack of recommendation to routinely screen patients with CD for small bowel cancer based on the low absolute risk, gastroenterologists may still choose to do so, especially those with persistently elevated celiac antibodies and/or lack of complete mucosal healing and continued symptoms. Choosing the best modality to screen for small bowel cancer is also challenging as there are no formal guidelines available; options include imaging (computed tomography or magnetic resonance, including enterography) and/or endoscopic procedures (eg, capsule endoscopy, push enteroscopy). It is important to note that CD can reside within any part of the small bowel and may not be easily visible with a “typical” endoscopy that usually only reaches the duodenum.
The best interval for routine serologic testing may vary among gastroenterologists; however, a recent expert review published by the American Gastroenterological Association (AGA) recommended follow-up serologic assessment 6 and 12 months after diagnosis followed by yearly assessment thereafter.6 Patients with continued symptoms may undergo serologic assessment more frequently, especially in light of the increased risk of small bowel cancer.
It is important to note that although societies such as the US Preventive Services Task Force (USPSTF) have found insufficient evidence to support CD screening in first-degree relatives of patients with CD, many physicians (both primary care and gastroenterologists) continue to do so.7 The best initial test is to check serum tissue transglutaminase IgA (tTG IgA) levels along with an IgA level.7 Physicians must also be aware that a positive tTG IgA test may eventually lead to an endoscopy with small bowel biopsies.
As a direct result of the small increased risk of small bowel cancer, patients may inquire about the overall mortality risk associated with CD. Several studies have found that CD may lead to increased risk of mortality and may be linked to the degree of inflammation seen on small bowel biopsies.8 A retrospective cohort study conducted by Ludvigsson et al evaluated 29,096 patients with CD over approximately 40 years. The study authors included 3 sets of patients: those with celiac disease (Marsh stage 3/villous atrophy), those with inflammation without villous atrophy (Marsh stages 1-2), and those with latent CD (positive celiac serology with normal mucosa). Patients with CD were found to have an increased risk of mortality (HR 1.39; 95% CI, 1.33-1.45), which was actually lower than those with only inflammation (HR 1.72; 95% CI, 1.64-1.79). Those with latent CD also had an increased HR of 1.35 (95% CI, 1.14-1.58). Mortality HR for CD decreased over time and was highest in the first year after diagnosis. Median follow-up ranged from approximately 6 to 9 years. The absolute mortality rate for CD was 10.4 (95% CI, 10.0-10.8). The most common causes of death in patients with CD were cardiovascular disease and cancer (details on types not provided).
Gastroenterologists will continue to struggle with how to best prevent and diagnose small bowel cancer in their patients with CD. Patients with CD should continue to be evaluated on a case-by-case basis until more data are available.
References
1. Oxentenko AS, Rubio-Tapia A. Celiac disease. Mayo Clin Proc. 2019;94(12):2556-2571. doi:10.1016/j.mayocp.2019.02.019
2. Emilsson L, Semrad C, Lebwohl B, Green PHR, Ludvigsson JF. Risk of small bowel adenocarcinoma, adenomas, and carcinoids in a nationwide cohort of individuals with celiac disease. Gastroenterology. 2020;159(5):1686-1694. doi:10.1053/j.gastro.2020.07.007
3. Askling J, Linet M, Gridley G, Halstensen TS, Ekström K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology. 2002;123(5):1428-1435. doi:10.1053/gast.2002.36585
4. Elfström P, Granath F, Ye W, Ludvigsson JF. Low risk of gastrointestinal cancer among patients with celiac disease, inflammation, or latent celiac disease. Clin Gastroenterol Hepatol. 2012;10(1):30-36. doi:10.1016/j.cgh.2011.06.029
5. Han Y, Chen W, Li P, Ye J. Association between coeliac disease and risk of any malignancy and gastrointestinal malignancy: a meta-analysis. Medicine (Baltimore). 2015;94(38):e1612. doi:10.1097/MD.0000000000001612
6. Husby S, Murrary JA, Katzka DA. AGA clinical practice update on diagnosis and monitoring of celiac disease-changing utility of serology and histologic measures: expert review. Gastroenterology. 2019;156(4):885-889. doi:10.1053/j.gastro.2018.12.010
7. USPSTF, Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for celiac disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2017;317(12):1252-1257. doi:10.1001/jama.2017.1462
8. Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F. Small-intestinal histopathology and mortality risk in celiac disease. JAMA. 2009;302(11):1171-1178. doi:10.1001/jama.2009.1320
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