title: Celiac disease or non-celiac gluten sensitivity? An approach to clinical differential diagnosis.
abstract: OBJECTIVE
  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 autoimmune 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 history 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 unlikely 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.
authors.affiliation: 1] Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA [2] Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Toufic A
authors.initials: TA
authors.lastname: Kabbani
authors.affiliation: Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Rohini R
authors.initials: RR
authors.lastname: Vanga
authors.affiliation: Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Leffler
authors.affiliation: Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Villafuerte-Galvez
authors.affiliation: Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Kumar
authors.initials: K
authors.lastname: Pallav
authors.affiliation: Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hansen
authors.affiliation: Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Rupa
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Dennis
authors.affiliation: Celiac Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Ciaran P
authors.initials: CP
authors.lastname: Kelly
mesh_terms: D000328:Adult; D000465:Algorithms; D015415:Biomarkers / Q000097:blood; D002446:Celiac Disease / Q000097:blood / Q000175:diagnosis* / Q000178:diet therapy; D003661:Decision Support Techniques; D003937:Diagnosis, Differential; D055050:Diet, Gluten-Free; D005260:Female; D005512:Food Hypersensitivity / Q000097:blood / Q000175:diagnosis* / Q000178:diet therapy; D005983:Glutens / Q000009:adverse effects*; D006683:HLA-DQ Antigens / Q000097:blood; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008962:Models, Theoretical; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D005983:Glutens