Histologic Follow-Up of People With Celiac Disease on a Gluten-Free Diet: Slow and Incomplete Recovery

Peter J. Wahab, MD, PhD, Jos W.R. Meijer, MD, Chris J.J. Mulder, MD, PhD


Am J Clin Pathol. 2002;118(3) 

In This Article

Abstract and Introduction

To assess histologic recovery in response to gluten withdrawal in celiac disease, 158 patients seen in our hospital during a 15-year period underwent follow-up small intestine biopsies (SIBs) within 2 years after starting a gluten-free diet; further SIBs were done if villous atrophy was present. A modified Marsh classification was used (IIIA, partial villous atrophy; IIIB, subtotal villous atrophy; IIIC, total villous atrophy).

Of patients with Marsh IIIA, IIIB, or IIIC lesions, histologic remission was seen in 65.0% within 2 years, 85.3% within 5 years, and 89.9% in long-term follow-up. Eleven patients (7.0%) with persisting (partial) villous atrophy had symptoms and signs of malabsorption and were considered to have refractory celiac disease; 5 of them developed an enteropathy-associated T-cell lymphoma. Children recovered up to 95% within 2 years and 100% in the long-term.

Histologic recovery in celiac disease after starting a gluten-free diet takes time and is incomplete or absent in a substantial subgroup of patients (10.1% villous atrophy after 5 years). Systematic follow-up of patients with celiac disease and the malabsorption syndrome and secondary complications is needed.

Celiac disease is a permanent state of intolerance to gluten, ie, alcohol-insoluble proteins of wheat, rye, and barley.[1,2] The immunologic response to gluten in gluten-sensitive people causes histologic abnormalities of the small intestinal mucosa, comprising influx of lymphocytes into the epithelium, crypthyperplasia, and, ultimately, villous atrophy.[3,4,5] This results in a diversity of symptoms and signs of malabsorption, including chronic diarrhea, abdominal distention, fatigue, weight loss, growth disturbances, and iron, folic acid, and other vitamin deficiencies. Treatment consists of starting a gluten-free diet, after which histologic findings and symptoms should normalize.

Histologic recovery of small intestinal mucosa is assumed to occur within 6 to 12 months after starting a gluten-free diet, simultaneously with clinical remission. Surprisingly, follow-up data on small intestinal recovery in celiac disease are scarce and contradictory. Shmerling and Franckx[6] reported complete normalization of the small intestinal mucosa in all of 91 children with celiac disease who were on a gluten-free diet. Congdon et al[7] found persisting villous atrophy in 2 of 10 children with celiac disease. Grefte et al[8] reported slow and incomplete histologic and functional recovery in 22 adults with celiac disease after 24 to 48 months of a gluten-free diet. Furthermore, Selby et al[9] demonstrated that persistent mucosal abnormalities seen in their series of patients with celiac disease were not due to the ingestion of trace amounts of gluten. This rejects the suggestion that persisting mucosal abnormalities in celiac disease usually are due to a poor compliance with a gluten-free diet.

Based on follow-up sugar absorption tests in patients with celiac disease while on a gluten-free diet, Uil et al[10] suggested a discongruency, ie, faster mucosal recovery in children than in adults. In clinical practice, we also have the impression that recovery in childhood and adult celiac disease is not equally time-related. For that matter, histologic recovery has not been defined specifically in the literature, and there is no discussion about persisting crypthyperplasia and lymphocytic infiltration. When villi reappear and normalize, do the hyperplasia of crypts and the intraepithelial infiltration of lymphocytes also disappear? And if they do not, is this without consequences, or are the patients still at risk for malabsorption and long-term complications such as osteopenia and malignancy?

The aim of the present study was to assess the histologic recovery profiles of patients with celiac disease, mainly adults, who were seen in our hospital during a 15-year period.


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