When the Diet Is Not Enough

Diet Non-Responsive Celiac Disease

Contrary to previous belief, it is now proven that the gluten-free diet (GFD) is not only a burden, but it is also ineffective for many patients. As a result of the difficulty in maintaining total avoidance of gluten while on a GFD, gluten contamination results in 50% or more of all diagnosed celiac patients continuing to have an active disease.
Patients who continue to have symptoms despite attempting to maintain a gluten-free diet are deemed to have diet non-responsive celiac disease. This is defined as persistent symptoms, signs or laboratory abnormalities typical of celiac disease despite 6–12 months of dietary gluten avoidance. The hypotheses to explain the sustained disease activity in many patients on a GFD include the potential for greater sensitivity to gluten in some patients and, particularly, continued gluten exposure given that it is virtually impossible to avoid gluten contamination in modern societies.

Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. American College of Gastroenterology. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013; 108:656-676.

Lee SK, Lo W, Memeo L, Rotterdam H, Green PH. Duodenal histology in patients with celiac disease after treatment with a gluten-free diet. Gastrointest Endosc 2003; 57:187-191.

Midhagen G, Hallert C. High rate gastrointestinal symptoms in celiac patients living on a gluten-free diet: controlled study. Am J Gastroenterol 2003; 98:2023-2026.

Hopper AD, Cross SS, Hurlstone DP, et al. Pre-endoscopy serological testing for coeliac disease: evaluation of a clinical decision tool. Br Med Journal 2007; 334:729.

Cranney A, Zarkadas M, Graham ID, et al. The Canadian Celiac Health Survey. Dig Dis Sci 2007; 52:1087-1095.

Refractory Celiac Disease

While rare (approximately 1 in 200 patients), the most serious complication of celiac disease is the development of a small bowel gastrointestinal T-cell lymphoma after many years of exposure to gluten. This malignant condition, which is no longer dependent of gluten or responsive to a gluten-free diet (GFD), is termed refractory celiac disease Type II (RCD-II). One in two patients with RCD-II will develop enteropathy-associated T cell lymphoma (EATL), which typically has a very poor prognosis and more than 50% mortality in many studies.

The treatment of RCD-II is difficult. Abnormal malignant lymphocytes are scattered in the whole small intestinal epithelium and usually in the stomach and colon, thereby precluding surgery. The prognosis of RCD-II is poor with death occurring within 3-10 years due to intractable diarrhea and/or high-grade lymphomas or, more rarely, metastasis of the low-grade proliferation to other tissues (e.g., skin, lungs). The treatment of high-grade lymphoma relies on surgical resection and chemotherapy, but the prognosis is very poor. An effective treatment for RCD-II remains one of the highest priorities.

Lebwohl B, Granath F, Ekbom A, et al. Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study. Ann Intern Med 2013; 159:169-175.

Nijeboer P, de Baaij LR, Visser O, et al. Treatment response in Enteropathy Associated T-cell Lymphoma; survival in a large multicenter cohort. Am J Hematol 2015; 90:493-498.