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Original Research |

Mucosal Healing and Risk for Lymphoproliferative Malignancy in Celiac Disease: A Population-Based Cohort Study

Benjamin Lebwohl, MD, MS; Fredrik Granath, PhD; Anders Ekbom, MD, PhD; Karin E. Smedby, MD, PhD; Joseph A. Murray, MD; Alfred I. Neugut, MD, PhD; Peter H.R. Green, MD; and Jonas F. Ludvigsson, MD, PhD
[+] Article, Author, and Disclosure Information

From Columbia University College of Physicians and Surgeons, New York, New York; Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; Mayo Clinic College of Medicine, Rochester, Minnesota; and Örebro University Hospital, Örebro, Sweden.

Grant Support: By The American-Scandinavian Foundation, Celiac Sprue Association, and grant KL2 TR000081 from the National Center for Advancing Translational Sciences of the National Institutes of Health (Dr. Lebwohl); Stockholm County Council (Dr. Ekbom); Strategic Research Program in Epidemiology's Young Scholar Award (Dr. Smedby); grants DK071003 and DK057892 from the National Institutes of Health (Dr. Murray); Örebro University Hospital, Karolinska Institutet, Swedish Society of Medicine, and grant 522-2A09-195 from the Swedish Research Council and the Swedish Celiac Society (Dr. Ludvigsson).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-3067.

Reproducible Research Statement: Study protocol and statistical code: Available from Dr. Ludvigsson (e-mail, jonasludvigsson@yahoo.com). Data set: Not available.

Corresponding Author: Jonas F. Ludvigsson, MD, PhD, Department of Pediatrics, Örebro University Hospital, SE-70185 Örebro, Sweden; e-mail, jonasludvigsson@yahoo.com.

Current Author Addresses: Drs. Lebwohl and Green: The Celiac Disease Center at Columbia University, 180 Fort Washington Avenue, Suite 936, New York, NY 10032.

Drs. Granath, Ekbom, and Smedby: Clinical Epidemiology Unit, Karolinska Institutet, Eugeniahemmet T2, SE-171 76, Stockholm, Sweden.

Dr. Murray: 200 First Street SW Mayo East 9, Rochester, MN 55905.

Dr. Neugut: Mailman School of Public Health, Columbia University, 722 West 168th Street, Room 725, New York, NY 10032.

Dr. Ludvigsson: Department of Pediatrics, Örebro University Hospital, SE-70185 Örebro, Sweden.

Author Contributions: Conception and design: B. Lebwohl, F. Granath, A. Ekbom, P.H.R. Green, J.F. Ludvigsson.

Analysis and interpretation of the data: B. Lebwohl, F. Granath, A. Ekbom, K.E. Smedby, J.A. Murray, A.I. Neugut, J.F. Ludvigsson.

Drafting of the article: B. Lebwohl, J.F. Ludvigsson.

Critical revision of the article for important intellectual content: B. Lebwohl, F. Granath, A. Ekbom, K.E. Smedby, J.A. Murray, A.I. Neugut, P.H.R. Green, J.F. Ludvigsson.

Final approval of the article: B. Lebwohl, F. Granath, A. Ekbom, K.E. Smedby, J.A. Murray, A.I. Neugut, P.H.R. Green, J.F. Ludvigsson.

Provision of study materials or patients: J.F. Ludvigsson.

Statistical expertise: B. Lebwohl, F. Granath, J.F. Ludvigsson.

Obtaining of funding: B. Lebwohl, A. Ekbom, J.F. Ludvigsson.

Administrative, technical, or logistic support: J.F. Ludvigsson.

Collection and assembly of data: J.F. Ludvigsson.

Ann Intern Med. 2013;159(3):169-175. doi:10.7326/0003-4819-159-3-201308060-00006
Text Size: A A A

Background: Celiac disease (CD) is associated with an increased risk for lymphoproliferative malignancy (LPM). Whether this risk is affected by the results of follow-up intestinal biopsy, performed to document mucosal healing, is unknown.

Objective: To examine the association between mucosal healing in CD and subsequent LPM.

Design: Population-based cohort study.

Setting: 28 pathology departments in Sweden.

Patients: 7625 patients with CD who had follow-up biopsy after initial diagnosis.

Measurements: The risk for LPM was compared with that of the general population by using expected rates. The rate of LPM in patients with persistent villous atrophy was compared with that of those with mucosal healing by using Cox regression.

Results: Among 7625 patients with CD and follow-up biopsy, 3308 (43%) had persistent villous atrophy. The overall risk for LPM was higher than that in the general population (standardized incidence ratio [SIR], 2.81 [95% CI, 2.10 to 3.67]) and was greater among patients with persistent villous atrophy (SIR, 3.78 [CI, 2.71 to 5.12]) than among those with mucosal healing (SIR, 1.50 [CI, 0.77 to 2.62]). Persistent villous atrophy compared with mucosal healing was associated with an increased risk for LPM (hazard ratio [HR], 2.26 [CI, 1.18 to 4.34]). The risk for T-cell lymphoma was increased (HR, 3.51 [CI, 0.75 to 16.34]) but not for B-cell lymphoma (HR, 0.97 [CI, 0.21 to 4.49]).

Limitation: No data on dietary adherence.

Conclusion: Increased risk for LPM in CD is associated with the follow-up biopsy results, with a higher risk among patients with persistent villous atrophy. Follow-up biopsy may effectively stratify patients with CD by risk for subsequent LPM.

Primary Funding Source: National Institutes of Health, The American-Scandinavian Foundation, Celiac Sprue Association, Örebro University Hospital, Karolinska Institutet, Swedish Society of Medicine, Swedish Research Council, and Swedish Celiac Society.

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Submit a Comment/Letter
Posted on August 12, 2013
Antonio Tursi, MD
Andrea Italy
Conflict of Interest: None Declared

Celiac disease and risk of lymphoproliferative disorders I read with interest the recent paper by Lebwohl and colleagues about the risk of lymphoproliferative disorders in celiac disease (CD) doesn’t obtaining mucosa healing (1). I am not fully convinced that a recommendation of follow-up biopsies can be accepted based on these observations. I think that we need additional information to validate these conclusions. In my opinion, there are several relevant limitations of the study. First of all, we are talking of “histological healing” rather than “mucosal healing”. In this way biopsies sampling as well as histological assessment is fundamental due to the often “patchy” villous atrophy in CD (2). In this study, authors collected data from reports from 28 pathology departments: are we sure that endoscopists sampled the duodenum in the same way in each of the involved centre? The lack of information about dietary compliance is the main limitation. In my experience, lack of adherence to GFD affect about half of CD patients developing complications (3). In particular 3/549 CD patients (0,54%) developed lymphoproliferative disorders under 7.13 years (range 1–15 years) of GFD: two of them were not fully compliant to GFD. absence of this information affects the overall. Adherence to GFD is therefore the key point to prevent complications, rather than follow-up biopsies.

Another point of discussion is the timing of follow-up biopsies. This is because histological recovery may take several years despite strict adherence to GFD, especially in older people (4). Interestingly, Lebwhol and colleagues reported that 26% of their CD population had follow-up biopsies performed during the first year after diagnosis. Thus, we can hypothesized that most of them had "persistent" villous atrophy only due because not in timing follow-up biopsies, and that this subgroup is coincidentally one at higher risk of lymphoproliferative disorders occurrence. Finally, we are talking of a CD complication with low incidence. Table 2 of the article shows that lymphoproliferative disorders had a prevalence ranging from 0% to 2% (often between 0% to 1%). A recent Italian study showed that the relative risks of undiagnosed CD (similar to not compliant CD not compliant to GFD) for gastrointestinal B- and T-cell lymphomas ranges from 1.0 to 2.0 for 1:100 CD prevalence (5). This seems to suggest that we should re-biopsy more than 100 CD patients in order to predict 1 case of lymphoproliferarive disorder. Also in this way, the cost/benefit of this approach is at least questionable.


1) Lebwohl B, Granath F, Ekbom A, Smedby KE, Murray JA, Neugut AI et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med 2013;159: 169-75

2) Ravelli A, Villanacci V, Monfredini C, Martinazzi S, Grassi V, Manenti S. How patchy is patchy villous atrophy?: distribution pattern of histological lesions in the duodenum of children with celiac disease. Am J Gastroenterol 2010;105: 2103-10

3) Tursi A, Elisei W, Giorgetti GM, Brandimarte G, Aiello F. Complications in celiac disease under gluten-free diet. Dig Dis Sci 2009;54(10): 2175-82

4) Tursi A, Brandimarte G, Giorgetti GM, Elisei W, Inchingolo CD, Monardo E et al. Endoscopic and histological findings in the duodenum of adults with celiac disease before and after changing to a gluten-free diet: a 2-year prospective study. Endoscopy 2006;38: 702-7

5) Elli L, Contiero P, Tagliabue G, Tomba C, Bardella MT. Risk of intestinal lymphoma in undiagnosed coeliac disease: results from a registered population with different coeliac disease prevalence. Dig Liver Dis 2012;44: 7437


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Summary for Patients

Risk for Lymphoma and the Results of Follow-up Gut Biopsies in Patients With Celiac Disease

The full report is titled “Mucosal Healing and Risk for Lymphoproliferative Malignancy in Celiac Disease. A Population-Based Cohort Study.” It is in the 6 August 2013 issue of Annals of Internal Medicine (volume 159, pages 169-175). The authors are B. Lebwohl, F. Granath, A. Ekbom, K.E. Smedby, J.A. Murray, A.I. Neugut, P.H.R. Green, and J.F. Ludvigsson.


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