Etiologies and Predictors of Diagnosis in Non-Responsive Celiac Disease

Abstract

Purpose: Nonresponsive celiac disease (NRCD), defined as a failure to respond to gluten free diet, is a common problem affecting 7 to 30% of celiac disease (CD) patients. The aim of this study was to determine the etiologies of NRCD and clinical factors predictive of final diagnosis. Methods: All cases of biopsy proven CD seen over the preceding 5 years were included. NRCD was defined as; 1. referral for evaluation of lack of response to a GFD, 2. failure of clinical symptoms or laboratory abnormalities of CD to improve within 6 months of strict GFD, 3. or recurrence of symptoms or abnormalities while on a strict GFD. Statistical significance was determined using two sample t-test, chi squared and Fisher's exact tests. Results: 113 individuals out of a total of 603 (18.7%) with CD were found to have NRCD. 39 of the 392 patients (9.9%) with CD who received their primary care at our institution developed NRCD compared to 19% of referrals (p < 0.001). Of the 99 cases diagnosed at time of review, the most common etiology of NRCD was gluten exposure, accounting for 36%. Other common etiologies of NRCD included irritable bowel syndrome (22%), refractory sprue (10%), lactose deficiency (8%) small intestinal bacterial overgrowth (SIBO) (6%), and microscopic colitis (6%). The remaining 13% consisted of eating disorders, peptic ulcer disease, gastroparesis, Crohn's disease, food allergies, common variable immune deficiency and duodenal adenocarcinoma. A limited number of factors were predictive of final diagnosis in NRCD. Weight loss was predictive of refractory sprue with an odds ratio of 31.1 (95% CI 5.9 to 163.1). An IgA anti-tTG titer above the upper limit of normal was predictive of gluten exposure at an odds ratio of 11.3 (95% CI 3.7 to 34.4) and a mean of 67 U/ml (range 2–135 U/ml) as was the absence of abdominal pain (p < 0.01). Irritable bowel syndrome (IBS) was associated with the presence of abdominal pain and absence of diarrhea (p < 0.01). Microscopic colitis and SIBO were also associated with diarrhea (p < 0.05). Female patients had a greater risk of being diagnosed with IBS (p= 0.04), but a decreased risk of refractory sprue (p= 0.006). Conclusions: NRCD is a common phenomenon affecting >10% of celiac patients. Most cases of NRCD result from one of a relatively limited group of disorders. High tTG, gender, and symptoms at presentation are predictive of final diagnosis. Eating disorders are a previously undescribed cause of NRCD which should be considered in appropriate clinical scenarios.