Celiac Disease Refractory to a Gluten-free Diet? Leann M. Mikesh, 1 Sheila E. Crowe, 2 Grant C. Bullock, 1 Nancy E. Taylor, 1 and David E. Bruns 1* CASE DESCRIPTION A 75-year-old woman from an outside hospital was referred because of continued signs and symptoms of celiac disease (gluten-sensitive enteropathy) that per- sisted despite self-reported adherence to a gluten-free diet. The patient reported excessive gas, bowel disten- sion, a 15-pound weight loss over the past few years, insomnia, and a rash over her lower extremities. The patient had required hospitalizations, intravenous flu- ids, and continuing therapy with corticosteroids for 6 months. A diagnosis of celiac disease had been made 6 years previously, based on (a) typical gastrointestinal signs and symptoms with negative stool cultures and Clos- tridium difficile toxin assay, (b) positive serology for celiac disease, (c) unremarkable colonoscopy with nor- mal random biopsy results, and (d) small-bowel biopsy results showing evidence of villous blunting with in- creased chronic inflammatory cells. At that time, the patient’s laboratory results included antigliadin anti- body (AGA) IgG 0.8 AU (10 AU), anti-AGA IgA 1.1 AU (5 AU), anti–tissue transglutaminase (tTG) IgA 9.2 AU (4 AU), and normal total IgA and IgA anti- endomysial antibody (EMA) values. A computed to- mographic scan was negative for lymphoma, and an upper gastrointestinal series and small-bowel follow- through barium x-ray were normal. Endoscopic biopsy results obtained during the previous 2 years showed continued villous atrophy with intraepithelial lympho- cytes. Shortly before the patient’s referral, repeat biop- sies showed villous blunting with increased chronic inflammation, findings confirmed by a gastrointestinal pathologist at our institution. The patient, a pleasant, frail-looking, elderly woman in no acute distress, was retired and married with 2 adult children. She denied smoking and alcohol use and had no family history of celiac disease, liver disease, or colon cancer. Her medical history was remarkable for placement of a carotid artery stent 5 years earlier. Physical examination was unremarkable except for the presence of a maculopapular rash inconsistent with dermatitis herpetiformis and with dependent distribu- tion over the lower legs. The patient’s blood pressure was 133/59 mmHg, pulse 51 beats/min, temperature 36.5 °C, and weight 59.4 kg. Laboratory results since her referral included vitamin B 12 245 ng/L [reference interval (RI), 251– 911 ng/L], iron 370 ug/L (RI, 400 –1450 g/L), anti- tTG IgA 13 AU (RI, 0 –20 AU), and 5'nucleotidase 22.1 U/L (RI, 4.0 –11.5 U/L). The patient met with a nutritionist and imple- mented recommended dietary changes to eliminate gluten. Her symptoms temporarily improved, with a return to normal bowel function, but after a short time her symptoms recurred. Results of further tests ex- cluded conditions known to complicate or coexist with celiac disease, including bacterial overgrowth, micro- scopic colitis, and lactose intolerance. Because the pa- tient’s symptoms were refractory to treatment and re- quired prolonged, continued use of corticosteroid therapy, esophagogastroduodenoscopy with duodenal biopsies was performed, and formalin-fixed small- bowel biopsy tissue samples were sent to the molecular diagnostic laboratory for additional testing. DISCUSSION CELIAC DISEASE Celiac disease is a T-cell driven, multifactorial chronic inflammatory disorder of the small intestine character- ized by mucosal inflammation, villous atrophy, and crypt hyperplasia; it has a prevalence of approximately 1% in the population. Among autoimmune diseases, celiac disease is unique in that an environmental trigger (gluten) and an autoantigen (tissue transglutaminase) have been identified (1). The main dietary sources of gluten are wheat, rye, barley, and oats, but the gluten in oats has not been found to contribute to celiac disease. Gluten is broken down into smaller peptides by gastric acid and digestive enzymes. In the intestine, tTG converts glutamine to glutamic acid, thereby increasing the affinity of the binding of gluten peptides in the cleft of HLA class II molecules. The modified peptides are inappropriately 1 Department of Pathology and 2 Division of Gastroenterology and Hepatology, Department of Medicine, University of Virginia School of Medicine, Charlottes- ville, VA. * Address correspondence to this author at the Department of Pathology, Box 800214, University of Virginia Medical School, Charlottesville, VA 22908; e-mail deb6j@virginia.edu. Received August 16, 2007; accepted November 20, 2007. Previously published online at DOI: 10.1373/clinchem.2007.095984 Clinical Chemistry 54:2 441–445 (2008) Clinical Case Study 441