Management of Refractory Celiac Disease

Karoly Horvath, MD, PhD, Alessio Fasano, MD, Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland.

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In This Article

Abstract and Introduction

Abstract

A small percentage of patients diagnosed with celiac disease fail to have a long-term favorable response to a strict gluten-free diet. These individuals continue to have symptoms and histologic abnormalities or have symptomatic relapse despite treatment with gluten-free diet and ultimately develop a potentially life-threatening disease known as refractory sprue. Based on data reported in recent studies, the majority of patients with refractory sprue have abnormal intraepithelial lymphocytes and a poor prognosis. The current hypothesis is that refractory sprue represents a transition state to intestinal lymphoma. The true prevalence of this disease entity is unknown. Future multicenter trials are therefore warranted to estimate its prevalence and establish clear therapeutic guidelines.

Introduction

Celiac disease (CD) is a gluten-sensitive enteropathy with a broad spectrum of clinical manifestations. Based on current knowledge, the initial step in disease pathogenesis is the deamidation of a toxic peptide fragment(s) from wheat, barley, and rye by tissue transglutaminase to form a complex. This peptide/HLA antigen complex triggers the immune response, which ultimately damages the small-intestinal mucosa. Clinically, the disease can be asymptomatic, and patients may have typical malabsorptive symptoms along with diarrhea, weight loss, and nutritional deficiencies.

The vast majority of patients diagnosed with CD respond to a gluten-free diet, with resolution of clinical symptoms and histologic and serologic recovery. Patients with malabsorption and histologic findings consistent with CD who are unable to achieve long-term remission on a gluten-free diet, and in whom other causes of flat mucosa have been excluded, are considered to suffer from unclassified or refractory sprue (RS). Prior to making the diagnosis of RS, all other causes of celiac-like enteropathy must be ruled out.

There are 3 discrete patterns of manifestations of RS. They are as follows: (1) only partial improvement on gluten-free diet; (2) no beneficial response to gluten-free diet; and (3) initial good response to gluten-free diet but relapse while still on this strict diet. Based on these manifestations, Ryan and colleagues defined 2 subgroups: primary RS and secondary RS. Patients with primary RS do not have full recovery on a gluten-free diet, whereas patients who have a full recovery and then relapse later have secondary RS. Ten of 21 patients with RS in a French multicenter study had initial clinical and histologic improvement on a gluten-free diet. All patients with RS have malabsorption and residual mucosal abnormalities of the small intestine.

There are no clear clinical or biological markers that predict the development of RS. The disorder manifests in adulthood and all reported cases have been in individuals over 20 years of age. Celiac serology tests were not performed in all of these reported cases. Ryan and colleagues reviewed the published reports and found that approximately only half of the patients had positive celiac serology tests. Cellier and associates reported that 17 (80%) of 21 patients with RS had antigliadin and/or antiendomysium antibodies prior to the gluten-free diet. With respect to the HLA-DQ2 association, 92% of the RS patients had this allele. The prevalence of the HLA-DQ2 association is similar to that found in uncomplicated celiac cases; however, this allele is known to be associated with many autoimmune diseases. Recent evidence suggests that RS comprises a heterogenous population of patients with diverse underlying causes. A small portion of these patients may have an adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies.

The primary clinical manifestations of RS are the absence of long-term beneficial response to a gluten-free diet and the worsening of symptoms that require therapeutic interventions. The presenting symptoms may be diarrhea, weight loss, abdominal pain, and refractory iron-deficiency anemia, or other nutritional deficiencies.

One of the endoscopic manifestations of RS is ulcerative jejunitis, which may progress to enteropathy-associated T-cell lymphoma (EATL). Both RS and EATL are characterized by the presence of a monoclonal T-cell population in the intestinal mucosa. In EATL, a similar monoclonal population that shows clonal identity with the lymphoma itself is also present in the enteropathic mucosa. Other patients have evident mucosal atrophy on endoscopy.

The histologic manifestations may include chronic mucosal atrophy, collagenous sprue, ulcerative jejunitis, subcryptal chronic inflammation, and mucosal thinning.

O'Mahony and coworkers estimated that 7% to 8% of adult celiac patients have RS. However, based on the sporadic reports, this appears to be an overestimation of the prevalence of RS. Table 1 summarizes the literature that has reported on more than single cases.

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