Clinical Review & Education JAMA | Review Celiac Disease and Nonceliac Gluten Sensitivity A Review Maureen M. Leonard, MD, MMSc; Anna Sapone, MD, PhD; Carlo Catassi, MD, MPH; Alessio Fasano, MD CME Quiz at IMPORTANCE The prevalence of gluten-related disorders is rising, and increasing numbers of jamanetwork.com/learning individuals are empirically trying a gluten-free diet for a variety of signs and symptoms. This review aims to present current evidence regarding screening, diagnosis, and treatment for celiac disease and nonceliac gluten sensitivity. OBSERVATIONS Celiac disease is a gluten-induced immune-mediated enteropathy characterized by a specific genetic genotype (HLA-DQ2 and HLA-DQ8 genes) and autoantibodies (antitissue transglutaminase and antiendomysial). Although the inflammatory process specifically targets the intestinal mucosa, patients may present with gastrointestinal signs or symptoms, extraintestinal signs or symptoms, or both, Author Affiliations: Center for Celiac suggesting that celiac disease is a systemic disease. Nonceliac gluten sensitivity Research and Treatment, Division of is diagnosed in individuals who do not have celiac disease or wheat allergy but who Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for have intestinal symptoms, extraintestinal symptoms, or both, related to ingestion Children, Boston, Massachusetts of gluten-containing grains, with symptomatic improvement on their withdrawal. The (Leonard, Sapone, Catassi, Fasano); clinical variability and the lack of validated biomarkers for nonceliac gluten sensitivity make Celiac Research Program, Harvard establishing the prevalence, reaching a diagnosis, and further study of this condition Medical School, Boston, Massachusetts (Leonard, Sapone, difficult. Nevertheless, it is possible to differentiate specific gluten-related disorders from Catassi, Fasano); Shire, Lexington, other conditions, based on currently available investigations and algorithms. Clinicians Massachusetts (Sapone); European cannot distinguish between celiac disease and nonceliac gluten sensitivity by symptoms, Biomedical Research Institute Salerno, Salerno, Italy (Catassi, as they are similar in both. Therefore, screening for celiac disease must occur before Fasano); Department of Pediatrics, a gluten-free diet is implemented, since once a patient initiates a gluten-free diet, Università Politecnica delle Marche, testing for celiac disease is no longer accurate. Ancona, Italy (Catassi). Corresponding Author: Alessio CONCLUSIONS AND RELEVANCE Celiac disease and nonceliac gluten sensitivity are common. Fasano, MD, Center for Celiac Research and Mucosal Immunology Although both conditions are treated with a gluten-free diet, distinguishing between celiac and Biology Research Center, disease and nonceliac gluten sensitivity is important for long-term therapy. Patients with Massachusetts General Hospital East, celiac disease should be followed up closely for dietary adherence, nutritional deficiencies, Bldg 114, 16th St (Mail Stop 114-3503), and the development of possible comorbidities. Charlestown, MA 02129-4404 ([email protected]). Section Editors: Edward Livingston, JAMA. 2017;318(7):647-656. doi:10.1001/jama.2017.9730 MD, Deputy Editor, and Mary McGrae McDermott, MD, Senior Editor. eliac disease is a chronic, small-intestinal immune- tion. There is strong evidence that celiac disease is an autoimmune C mediated enteropathy initiated by exposure to dietary disease triggered by the ingestion of gluten present in wheat, bar- gluten in genetically predisposed individuals and charac- ley, and rye in genetically predisposed individuals. The prevalence terized by specific autoantibodies against tissue transglutaminase of celiac disease in the general population is 1%, with regional dif- 2(anti-tTG2),endomysium,and/ordeamidatedgliadinpeptide.1 ferences (Table 1).4 Celiac disease can affect any human organ or tis- Althoughupto40%ofthe population carries the genotype HLA-DQ2 sue (Table 1 and Table 2).6 or HLA-DQ8,whichisrequiredforthedevelopmentofceliacdis- Nonceliac gluten sensitivity is a term used to describe individu- ease, only 2% to 3% of HLA-DQ2 or HLA-DQ8 carriers subsequently als who have intestinal signs or symptoms, extraintestinal signs develop celiac disease.2 Celiac disease, once considered a rela- or symptoms, or both, related to ingestion of gluten-containing tively rare gastrointestinal condition affecting almost exclusively grains (Table 2), with improvement when these are removed from young white children, can develop at any age and can affect almost apatient’sdiet.Thefrequencyofnonceliacglutensensitivity any race. Celiac disease was first described by Samuel Gee in 1887. is unknown owing to the lack of validated biomarkers, but it is Wheat was hypothesized as the possible offending agent by thought to be more common than celiac disease. Wheat allergy, the William Dicke in 1941.3 third gluten-related disorder, which will not be addressed in this The epidemiology, clinical presentation, pathophysiology, and review, is defined as an adverse type-2 helper T-cell immunologic management of the disease have changed since its initial descrip- reaction to wheat proteins and typically presents soon after wheat jama.com (Reprinted) JAMA August 15, 2017 Volume 318, Number 7 647 © 2017 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/ by Robert Rountree on 09/01/2017 Clinical Review & Education Review Celiac Disease and Nonceliac Gluten Sensitivity Table 1. Prevalence of Celiac Disease in the General Population Scholar (January 15, 2010, to April 18, 2017) were searched using and in At-Risk Groupsa the search terms coeliac, celiac, non-celiac, non-coeliac, gluten, and wheat sensitivity,aloneandincombination.Publicationsin Prevalence, % the past 5 years were selected in addition to commonly refer- General Population enced and highly regarded older publications. Reference lists of Algeria 5.6 articles identified by this search strategy were selected. Review Argentina 0.6 articles and book chapters were cited to provide readers with Australia 0.4 additional details and sources of additional references. Brazil 0.5 Burkina Fasu 0 Egypt 0.5 Finland 1.0-2.4 Results Germany 0.2 India 0.3-1.0 Pathophysiology Iran 0.5-1.0 Gluten as Environmental Trigger of Gluten-Related Disorders Ireland 0.8 Gluten is a mixture of gliadins and glutenins, complex pro- teins unusually rich in prolines and glutamines that are not Italy 0.9-1.0 completely digestible by intestinal enzymes.9 The final product Libya 0.8 of this partial digestion is a mix of peptides that can trigger The Netherlands 0.5 host responses (increased intestinal permeability and innate New Zealand 1.2 +/− adaptive immune response) that closely resemble those Portugal 0.7 instigated by the exposure to gastrointestinal pathogens10-13 Russia 0.2 (Figure 1). Spain 0.3-1.4 Sweden 0.5-2.9 Normal Phsyiologic Events That Contribute to the Pathogenesis of Tunisia 0.6 Celiac Disease and Nonceliac Gluten Sensitivity Turkey 0.6-1.0 Gluten Translocation From Lumen to Lamina Propria (Paracellular vs United Kingdom 0.9-1.5 Transcellular) | Previous studies have shown that gliadin can United States 0.3-0.9 cause an immediate and transient increase in gut permeability.9,13 Mean (weighted) 1.0 This permeating effect is secondary to the binding of spe- At-Risk Groups cific undigestible gliadin fragments to the CXCR3 chemokine Type 1 diabetes 3-12 receptor with subsequent release of zonulin, a modulator of inter- Autoimmune thyroid disease 3 cellular tight junctions (Figure 1).14 This process takes place in all Autoimmune liver disease 13.5 individuals who ingest gluten. For the majority, these events do Down syndrome 5.5 not lead to abnormal consequences. However, these same events Turner syndrome 6.5 can lead to an inflammatory process in genetically predisposed Williams syndrome 9.5 individuals when the immunologic surveillance system mistakenly IgA deficiency 3 recognizes gluten as a pathogen. Thus, this normal physiologic IgA nephropathy 4 process is also essential to the development of celiac disease and Juvenile idiopathic arthritis 1.5-2.5 nonceliac gluten sensitivity in at-risk individuals. Additionally, a Modified from Husby et al.4 Data on at-risk groups were collected from there is evidence that during the acute phase of celiac disease, different, Western populations.5 A prevalence range indicates that more than 1 gluten can also cross the intestinal barrier through the transcellu- study is available. lar pathway via transferrin receptor CD71, once tolerance to glu- ten has been lost15 (Figure 1). ingestion, with signs of anaphylaxis such as swelling or itching of the mouth, throat, and skin; nasal congestion; watery eyes; and dif- The Innate Immune Response | Innate immunity plays a critical ficulty breathing. Wheat allergy is more common in children, with role in initiating celiac disease and possibly nonceliac glu- reported prevalence between 2% and 9% in children and 0.5% ten sensitivity. Cytokines such as interleukin (IL) 15 and interferon and 3% in adults.8 alfa can prime the innate immune response by polarizing This review provides an evidence-based update of the patho- dendritic cells and intraepithelial lymphocyte function.15,16 physiology, diagnosis, treatment, and implications of celiac dis- These mucosal events, along with the breach of the epithelial ease and nonceliac gluten sensitivity. barrier function secondary to the gliadin-mediated zonulin re- lease,14