Mucosal Recovery and Mortality in Adults with Celiac Disease After Treatment With a Gluten-free Diet

Alberto Rubio-Tapia MD; Mussarat W Rahim MBBS; Jacalyn A See MS; RD; LD; Brian D Lahr MS; Tsung-Teh Wu MD; Joseph A Murray MD


Am J Gastroenterol 

In This Article

Abstract and Introduction


Objectives: Clinical response is typically observed in most adults with celiac disease (CD) after treatment with a gluten-free diet (GFD). The rate of mucosal recovery is less certain. The aims of this study were (1) to estimate the rate of mucosal recovery after GFD in a cohort of adults with CD, and (2) to assess the clinical implications of persistent mucosal damage after GFD.
Methods: The study group included adults with biopsy-proven CD evaluated at the Mayo Clinic who had duodenal biopsies at diagnosis and at least one follow-up intestinal biopsy to assess mucosal recovery after starting a GFD. The primary outcomes of interest were mucosal recovery and all-cause mortality.
Results: Of 381 adults with biopsy-proven CD, 241 (73% women) had both a diagnostic and follow-up biopsy available for re-review. Among these 241, the Kaplan–Meier rate of confirmed mucosal recovery at 2 years following diagnosis was 34% (95% confidence interval (CI): 27–40%), and at 5 years was 66% (95% CI: 58–74%). Most patients (82%) had some clinical response to GFD, but it was not a reliable marker of mucosal recovery (P=0.7). Serological response was associated with confirmed mucosal recovery (P=0.01). Poor compliance to GFD (P<0.01), severe CD defined by diarrhea and weight loss (P<0.001), and total villous atrophy at diagnosis (P<0.001) were strongly associated with persistent mucosal damage. There was a trend toward an association between achievement of mucosal recovery and a reduced rate of all-cause mortality (hazard ratio=0.13, 95% CI: 0.02–1.06, P=0.06), adjusted for gender and age.
Conclusions: Mucosal recovery was absent in a substantial portion of adults with CD after treatment with a GFD. There was a borderline significant association between confirmed mucosal recovery (vs. persistent damage) and reduced mortality independent of age and gender. Systematic follow-up with intestinal biopsies may be advisable in patients diagnosed with CD as adults.


Celiac disease (CD) is triggered by the ingestion of gluten present in cereals such as wheat, barley, and rye in genetically susceptible individuals.[1] Although severe complications can develop if unrecognized and untreated, a gluten-free diet (GFD) is an effective treatment that can alleviate symptoms and normalize antibodies and the intestinal mucosa in patients with CD.[2,3]

Substantial clinical response is observed in most patients with CD after only a few weeks on a GFD.[4] However, mucosal recovery does not occur in all patients with CD in whom complete clinical response is achieved.[5,6] Also, there are asymptomatic cases of CD in the presence of severe mucosal damage.[7]

Up to 95% of CD cases diagnosed during childhood may have complete intestinal mucosal recovery within 2 years after starting a GFD.[8] The rate of mucosal recovery after treatment with a GFD in adults with CD is less certain.[5,6,9–12] Complete recovery of the intestinal mucosa in adults with CD may be obtainable, but often requires longer than 12 months of strict adherence to GFD.[2,13] Besides the obvious issue of poor adherence to GFD, other factors involved in persistence of intestinal damage in adults with treated CD are less clear.[14] Documentation of mucosal recovery after treatment with a GFD may be clinically relevant because persistent mucosal damage appears to increase the risk of severe complications in patients with CD, even in the absence of symptoms.[15] Persistent mucosal villous atrophy without symptoms has not been traditionally considered within the spectrum of refractory celiac disease, a rare condition characterized by severe malabsorption and persistent villous atrophy despite strict adherence to GFD.[16–18] However, a minority of patients with treated CD, without symptoms but with persistent mucosal villous atrophy, may develop overt refractory celiac disease or other complications over time.[15]

Diagnosed clinically detected CD carries a modestly increased risk of mortality mainly attributable to malignancies, though strict adherence to a GFD may reduce this risk.[19–24] Two studies have suggested a significantly increased risk of mortality over time in patients with undiagnosed CD.[25,26] However, the association of undiagnosed CD with increased mortality is not universal nor is the association with increased malignancy.[27,28] Recently, a large study from Sweden showed an elevated risk of death among patients with CD (Marsh stage 3), duodenal inflammation (Marsh stage 1–2), or latent CD, the latter being defined as positive celiac serology in individuals with normal mucosa (Marsh stage 0).[29,30] The effect of persistent mucosal damage, despite treatment with a GFD, on "hard" outcomes (e.g., mortality) is unknown, as are the clinical factors associated with the rate of mucosal recovery. It can be hypothesized that (1) persistent mucosal damage in adults with treated CD can in some cases lead to an increased risk of death over time, and (2) there are clinical factors that may be associated with a reduced rate of mucosal recovery.

The aims of the study were to (1) estimate the rate of mucosal recovery in response to a GFD in adults with biopsy-proven CD, (2) identify clinical factors associated with persistent mucosal damage, and (3) determine whether the persistence of mucosal damage after treatment with a GFD in adults with CD is associated with increased mortality.


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