Refractory celiac disease (RCD) is a rare but life-threatening complication of celiac disease (CD), and only 1 pediatric case has been reported. We report a case of a 14-year-old girl with CD presenting with persistent symptoms and positive tissue celiac-specific antibodies despite a gluten-free diet. Push enteroscopy showed jejunal scalloping and partial villous atrophy on histology. She was diagnosed with RCD and treated with infliximab with subsequent complete serological and histological remission.
Celiac disease (CD) is an autoimmune disorder that causes intestinal inflammation in response to gluten in genetically predisposed individuals. Symptoms range from abdominal pain, bloating, and fatigue to malabsorption, diarrhea, and growth failure. Refractory celiac disease (RCD) is a rare and life-threatening complication of CD and is defined as persistence of symptoms and/or persistent villous atrophy with increased intraepithelial lymphocytes (IELs) despite adherence to a strict gluten-free diet (GFD) for more than 12 months.1,2 Only 2–10% of adult patients with CD develop RCD.2 Type I RCD has normal IELs and normal expression of surface CD3, CD4, CD103, with polyclonal T-cell receptor γ-gene rearrangement.3 These IELs are indistinguishable from the infiltrate found in CD. Type II RCD is characterized by lack of surface IEL CD3, CD4, or CD8, and has a monoclocal T-cell receptor γ-gene rearrangement.3 Type I is more likely to respond to immunosuppressive therapy and has a better 5-year survival rate, with a relatively benign course.3
A 14-year-old female presented with a 2-month history of intermittent abdominal pain, nausea, bloating, and diarrhea. She was diagnosed with CD, with a positive celiac serology (tissue transglutaminase [tTG] IgA 100 U/mL) and Marsh 3b duodenal histology (Figure 1). GFD resulted in mild symptomatic improvement and a drop in the tTG IgA to 11 U/mL. However, abdominal pain and poor weight gain persisted through 10 months of a strict GFD at home. Endomysial antibody titers were negative. Genetic testing was positive for HLA-DQ2 and negative for HLA-DQ8.
Figure 1. Duodenal histology showing marked villous blunting and intraepithelial lymphocytosis.
Our nutritionist performed a detailed dietary assessment, which did not reveal any gluten exposure. Under close supervision of our nutritionist, the patient tried a modified diet excluding all grains and processed foods for 3 months with no improvement. Subsequently, a diet of only elemental nutritional supplements was attempted for 4 weeks, followed by complete bowel rest with total parenteral nutrition (TPN) for 4 weeks, each with no improvement.
Repeat upper endoscopy and colonoscopy was completely normal. Tests were negative for giardiasis, tropical sprue, post-infectious enteritis, inflammatory bowel disease (including negative p-ANCA, anti-Saccharomyces cerevisiae antibodies, anti-OmpC, and anti-CBir serology), small intestinal bacterial overgrowth, lactase deficiency, HIV, common variable immunodeficiency, eosinophilic gastroenteritis, autoimmune enteropathy, and Mycobacterium tuberculosis. Video capsule endoscopy showed jejunal scalloping (Figure 2). Jejunal biopsies obtained via push enteroscopy showed active CD, Marsh 3a lesions with villous blunting and increased intraepithelial lymphocytes (50 IELs/100 enterocytes). After 20 months of GFD and persistent villous atrophy, the patient was diagnosed with RCD.
Figure 2. Capsule endoscopy showing small intestinal scalloping.
Immunostaining of the IELs showed normal CD3 and CD8-positive lymphocytes, and T-cell rearrangement (TCR) analysis showed polyclonal T-cell bands, consistent with the diagnosis of type I RCD. The patient was offered prednisone, budesonide, and azathioprine, but the patient and her family did not want corticosteroids due to the patient’s high BMI (>97th percentile), severe acne, a prior diagnosis of polycystic ovarian syndrome, and a family history of hypertension. The patient was started on infliximab, and symptoms and serology improved over 8 months of treatment with normalization of mucosa on jejunal biopsy. The patient continues to be on a GFD while receiving infliximab every 8 weeks, and remains asymptomatic.
RCD is a rare occurrence in pediatrics, and to our knowledge, only 1 case has been reported.4 The most reliable method to screen for compliance with GFD is detailed nutritional evaluation, and it is imperative to confirm strict GFD compliance for at least 12 months before considering RCD. The presence of celiac antibodies does not necessarily exclude the diagnosis of RCD, as 19–30% of patients with RCD continue to have positive celiac serology.5 Not all patients with ongoing gluten exposure develop celiac antibodies,6,7 so serological titers are not a true reflection of gluten exposure.
Once the diagnosis of RCD is established, treatment options are limited. Prednisone and budesonide, with or without azathioprine, are used to treat type I RCD and may result in complete histological healing.6,8 However, there have been case reports of complete remission of type I RCD with use of anti-tumor necrosis factor (TNF)-α agents,9-14 and other therapeutic agents like campath,14 cladribine,15 and cyclosporine A.14
We report a rare occurrence of RCD in a pediatric patient, highlight the importance of a rigorous work-up before a diagnosis of RCD is considered, and show that infliximab is a potential treatment option for pediatric type I RCD. As RCD is rare and its treatment and long-term prognosis are different from CD, it is important to arrive at this diagnosis in a very careful and systematic manner.
Author contributions: N. Rawal designed and drafted the manuscript, and is the article guarantor. W. Twaddell collected data and processed the histopathology specimens. A. Fasano reviewed the manuscript and advised regarding the celiac disease content. S. Blanchard designed and drafted the manuscript, and reviewed the final version of the manuscript. A. Safta initiated the case report, advised the authors, and reviewed the final version of the manuscript.
Financial disclosure: None to report.
Informed consent was obtained for this case report.
Correspondence: Nidhi Rawal, MD, MPH, University of Maryland Medical Center, 22 S Greene St, Suite N5W68, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Baltimore, MD 21210 (firstname.lastname@example.org).
Received: July 29, 2014; Accepted: December 10, 2014
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