nature publishing group ORIGINAL CONTRIBUTIONS COLON/SMALL BOWEL 1 © 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY see related editorial on page x INTRODUCTION he pathogenesis of celiac disease (CD) is one of the best under- stood among autoimmune diseases, given our knowledge of the environmental, genetic, and immunologic basis of the disease (1). CD is precipitated by the ingestion of barley, wheat, and rye, which trigger immunohistopathological changes in genetically susceptible subjects (1,2). he gluten-free diet (GFD) remains the cornerstone treatment of CD (1). However, CD is not the sole clinical entity that responds to the GFD (3). Recently, there has been growing interest in subjects who report gastrointestinal (GI) symptoms responsive to the GFD in the absence of documented CD (4–8). his population shares characteristics of both CD and irritable bowel syndrome, but it does not meet the diag- nostic criteria for either disorder (4–6). Consequently, a new disor- der known as non-celiac gluten sensitivity (NCGS) has emerged to describe this increasingly frequent presentation to gastroenterologists and primary care practitioners (4–12). Currently, the lack of speciic diagnostic criteria preclude the study of NCGS prevalence in the Celiac Disease or Non-Celiac Gluten Sensitivity? An Approach to Clinical Differential Diagnosis Toufic A. Kabbani, MD, MPH 1,2 , Rohini R. Vanga, MD 1 , Daniel A. Leffler, MD, MS 1 , Javier Villafuerte-Galvez, MD 1 , Kumar Pallav, MD 1 , Joshua Hansen, MS 1 , Rupa Mukherjee, MD 1 , Melinda Dennis, MS, RD, LDN 1 and Ciaran P. Kelly, MD 1 OBJECTIVES: Differentiating between celiac disease (CD) and non-celiac gluten sensitivity (NCGS) is important for appropriate management but is often challenging. METHODS: We retrospectively reviewed records from 238 patients who presented for the evaluation of symptoms responsive to gluten restriction without prior diagnosis or exclusion of CD. Demographics, presenting symptoms, serologic, genetic, and histologic data, nutrient deficiencies, personal history of autoim- mune diseases, and family history of CD were recorded. NCGS was defined as symptoms responsive to a gluten-free diet (GFD) in the setting of negative celiac serology and duodenal biopsies while on a gluten-containing diet or negative human leukocyte antigen (HLA) DQ2/DQ8 testing. RESULTS: Of the 238 study subjects, 101 had CD, 125 had NCGS, 9 had non-celiac enteropathy, and 3 had indeterminate diagnosis. CD subjects presented with symptoms of malabsorption 67.3% of the time compared with 24.8% of the NCGS subjects ( P < 0.0001). In addition, CD subjects were significantly more likely to have a family history of CD ( P = 0.004), personal history of autoimmune diseases ( P = 0.002), or nutrient deficiencies ( P < 0.0001). The positive likelihood ratio for diagnosis of CD of a > 2× upper limit of normal IgA trans-glutaminase antibody (tTG) or IgA/IgG deaminated gliadan peptide antibody (DGP) with clinical response to GFD was 130 (confidence interval (CI): 18.5– 918.3). The positive likelihood ratio of the combination of gluten-responsive symptoms and negative IgA tTG or IgA/IgG DGP on a regular diet for NCGS was 9.6 (CI: 5.5–16.9). When individuals with negative IgA tTG or IgA/IgG DGP also lacked symptoms of malabsorption (weight loss, diarrhea, and nutrient deficiencies) and CD risk factors (personal history of autoimmune diseases and family his- tory of CD), the positive likelihood ratio for NCGS increased to 80.9. CONCLUSIONS: On the basis of our findings, we have developed a diagnostic algorithm to differentiate CD from NCGS. Subjects with negative celiac serologies (IgA tTG or IgA/IgG DGP) on a regular diet are unlike- ly to have CD. Those with negative serology who also lack clinical evidence of malabsorption and CD risk factors are highly likely to have NCGS and may not require further testing. Those with equivocal serology should undergo HLA typing to determine the need for biopsy. Am J Gastroenterol advance online publication, 11 March 2014; doi:10.1038/ajg.2014.41 1 Celiac Center, Beth Israel Deaconess Medical Center , Boston, Massachusetts, USA; 2 Harvard School of Public Health, Boston, Massachusetts, USA. Correspondence: Toufic A. Kabbani, MD, MPH, Celiac Center, Beth Israel Deaconess Medical Center , 330, Brookline Avenue, Boston, Massachusetts 02215, USA. E-mail: tok043@mail.harvard.edu Received 11 July 2013; accepted 14 January 2014