Guideline sources The following summarized guidelines for the evaluation and management of celiac disease (CD) are prepared by our editorial team based on guidelines from the American College of Gastroenterology (ACG 2023; 2013), the European Society of Gastrointestinal Endoscopy (ESGE 2023), the American Diabetes Association (ADA 2023), the United European Gastroenterology (UEG/ESPEN 2023), the American Gastroenterological Association (AGA 2022; 2020; 2019), the European Academy of Dermatology and Venereology (EADV 2021), the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN 2020), the European Society for the Study of Coeliac Disease (ESsCD 2019), the U.S. Preventive Services Task Force (USPSTF 2017), and the British Society of Gastroenterology (BSG 2011). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 14 15 16 16 17 Definition https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 1/15 6/29/23, 3:46 AM Celiac disease Pathway CD is an immune-mediated inflammatory enteropathy triggered by gluten exposure in genetically susceptible individuals. 14 Epidemiology In patients with CD, the ingestion of gluten triggers an innate and adaptive immune response, leading to tissue inflammation and damage. Characteristically, deamidated gluten and the self- protein TG2 both become targets of highly disease specific B-cell responses. 16 17 Pathophysiology In the United States, the prevalence of CD is estimated at 500-1000 persons per 100,000 population. 15 Disease course CD may result in disease manifestations related to malabsorption (e.g. electrolyte imbalances, osteoporosis, infertility, neurological disorders), manifestations of extra-intestinal autoimmunity (dermatitis herpetiformis), or manifestations of neoplastic complications (increased risk of enteropathy associated T-cell lymphoma and small bowel adenocarcinoma). 16 Prognosis and risk of recurrence The majority of patients will respond to a lifelong gluten-free diet which is the cornerstone of therapy. 14 Calculator Calculator Diagnostic criteria for celiac dis Modified Marsh classification of Guidelines 1. Screening and diagnosis Indications for screening, asymptomatic individuals: As per ACG 2023 guidelines, do not obtain mass screening for CD in the community. Obtain case finding to increase the detection of CD in clinical practice. D As per USPSTF 2017 guidelines, insufficient evidence to assess the balance of benefits and harms of screening for CD in asymptomatic individuals. I As per ACG 2013 guidelines, consider obtaining testing for CD in asymptomatic individuals with a first-degree family member having a confirmed diagnosis of CD. B https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 2/15 6/29/23, 3:46 AM Celiac disease Pathway Indications for screening (family relatives): obtain screening in asymptomatic first-degree family members of patients with CD. B Show 3 more Indications for screening (iron deficiency anemia): obtain screening for CD in all patients with iron deficiency anemia. B Indications for screening, type 1 diabetes: As per ADA 2023 guidelines: Screen young patients with T1DM for CD by measuring anti-tTG (IgA) with documentation of normal total serum IgA levels, soon after the diagnosis of diabetes, or anti-tTG (IgG) and deamidated gliadin antibodies if IgA is deficient. B Repeat screening within 2 years of diabetes diagnosis and then again after 5 years and consider obtaining more frequent screening in patients with symptoms or a first-degree relative with CD. B As per ESsCD 2019 guidelines, obtain regular screening for CD in patients with T1DM. A Indications for testing: As per ESsCD 2019 guidelines: Obtain serology testing for CD in adult patients with symptoms, signs, or laboratory evidence suggestive of malabsorption. A Evaluate and exclude the diagnosis of CD in patients with unexplained elevation of serum aminotransferase levels. A As per ACG 2013 guidelines, obtain testing for CD in patients with symptoms, signs, or laboratory evidence suggestive of malabsorption, such as chronic diarrhea with weight loss, steatorrhea, postprandial abdominal pain, and bloating. A Show 3 more Diagnosis, seropositive: As per EADV 2021 guidelines, consider diagnosing enteropathy even without biopsy in pediatric patients with very high levels of serum anti-tTG ( 10 times above the ULN) confirmed by endomysial antibodies positivity from a separate blood sample. As per AGA 2019 guidelines, diagnose CD in patients with high levels (> 10 times the ULN) of anti-tissue transglutaminase IgA. Recognize that the combination of strongly positive anti-tissue transglutaminase IgA with positive endomysial antibodies in a second blood sample has a positive predictive value of 100% for CD. E As per ESsCD 2019 guidelines, suspect the diagnosis of CD in symptomatic patients and/or in patients with Marsh 1 histology and abnormal laboratory tests, if both anti-tissue transglutaminase and endomysial antibodies are positive. B Show 6 more Diagnosis (seronegative): Obtain endoscopic evaluation after 1-3 years on a gluten-free diet to evaluate improvements in villous atrophy in patients with suspected seronegative CD with villous atrophy and genetic risk https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 3/15 6/29/23, 3:46 AM Celiac disease Pathway factors for CD. Confirm a diagnosis of seronegative CD based on clinical and histologic markers of improvement on the gluten-free diet. B Consider using negative HLA testing results to rule out CD in seronegative patients. C Differential diagnosis: As per AGA 2020 guidelines, assess medication history with attention to ARBs (such as olmesartan) and travel history to identify potential etiologies of villous atrophy and guide additional testing. B As per ESsCD 2019 guidelines, evaluate for other possible causes of IBS-like symptoms in patients with a negative gluten challenge. B As per ACG 2013 guidelines: Differentiate CD from non-celiac gluten sensitivity in order to identify the risk for nutritional deficiency states, complications of CD, the risk for CD and associated disorders in family members, and to influence the degree and duration of adherence to the gluten-free diet. B Assess for etiologies other than CD in patients with lymphocytic infiltration of the intestinal epithelium in the absence of villous atrophy, as this finding is not specific to CD. A 2. Diagnostic investigations Medical history: Elicit a thorough medication history with attention to ARBs (such as olmesartan) and a travel history to identify potential etiologies of villous atrophy and guide additional testing. B Obtain a careful review of the patient's diet. B Serologic testing: As per ACG 2023 guidelines, consider obtaining a combination of tissue transglutaminase IgA and endomysial antibodies in a second blood sample for the diagnosis of CD in pediatric patients. Consider obtaining the same tests in symptomatic adult patients unwilling or unable to undergo upper gastrointestinal endoscopy. C As per EADV 2021 guidelines, obtain IgA antibodies against tissue transglutaminase-2 in all patients with suspected CD, as they are specific markers of gluten-induced enteropathy. B Show 2 more As per AGA 2020 guidelines, obtain serologic testing for accurate diagnosis of CD. B Show 2 more As per ESPGHAN 2020 guidelines, obtain anti-tissue transglutaminase IgA as the initial test, regardless of age, in patients with normal serum IgA levels for age. A As per AGA 2019 guidelines, obtain the following serologic tests for the detection and diagnosis of CD: anti-tissue transglutaminase IgA total IgA anti-endomysial IgA (less frequently). E https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 4/15 6/29/23, 3:46 AM Celiac disease Pathway Show 4 more As per ESsCD 2019 guidelines, obtain anti-tissue transglutaminase IgA as the preferred single test for detection of CD at any age. A Show 6 more As per ACG 2013 guidelines, obtain anti-tissue transglutaminase IgA as the preferred single test for the detection of CD in patients > 2 years of age. A Show 2 more HLA genotyping: As per ESPGHAN 2020 guidelines: Do not obtain HLA testing in patients with positive anti-tissue transglutaminase IgA qualifying for the diagnosis of CD with biopsies or with high serum levels of anti-tissue transglutaminase IgA ( 10 times the ULN) and positive endomysial antibodies. D Recognize that the risk of CD is very low in patients with negative HLA-DQ2/DQ8, while positive results do not confirm the diagnosis. A As per AGA 2019 guidelines: Avoid obtaining HLA-DQ2/DQ8 for the diagnosis of CD. D Consider obtaining HLA-DQ2/DQ8 to rule out the diagnosis of CD in patients: with negative serology results and histologic changes without serologic confirmation at the time of diagnosis with a historic diagnosis, especially as very young pediatric patients before the introduction of CD-specific serology. E As per ESsCD 2019 guidelines, obtain HLA-DQ2/DQ8 testing and assess the response to a gluten-free diet in patients with seronegative CD (negative IgA- and IgG-based celiac serology) after excluding other causes of seronegative villous atrophy. B Show 3 more As per ACG 2013 guidelines: Avoid obtaining routine HLA-DQ2/DQ8 testing for the initial diagnosis of CD. D Obtain HLA-DQ2/ DQ8 testing to rule out CD in selected clinical situations, such as: equivocal small bowel histological finding (Marsh 1-2) in seronegative patients evaluation of patients on a gluten-free diet if no testing for CD was done before a gluten-free diet patients with discrepant CD-specific serology and histology patients with suspicion of refractory CD, where the original diagnosis of CD remains in question patients with Down's syndrome. B Gluten challenge: As per ESsCD 2019 guidelines, perform gluten challenge in patients already following a gluten- free diet before testing, if serology is negative and HLA-DQ2/DQ8 is positive. A https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 5/15 6/29/23, 3:46 AM Celiac disease Pathway As per ACG 2013 guidelines, avoid using symptoms or symptom response to a gluten-free diet alone for the diagnosis of CD, as these do not differentiate CD from non-celiac gluten sensitivity. D Intestinal permeability tests: As per ESsCD 2019 guidelines, do not obtain intestinal permeability tests for the diagnosis of CD, as they are neither specific nor sensitive. D As per ACG 2013 guidelines, do not obtain intestinal permeability tests or D-xylose for the diagnosis of CD, as they are neither specific nor sensitive. D Stool and saliva studies: do not obtain stool studies or salivary tests for the diagnosis of CD. D Evaluation for micronutrient deficiencies: As per ESsCD 2019 guidelines, obtain testing for deficiencies of the following essential micronutrients in adult patients with newly diagnosed CD: iron folic acid vitamin D vitamin B12. B As per ACG 2013 guidelines, evaluate and treat for micronutrient deficiencies in patients with newly diagnosed CD. Consider testing for deficiency in: iron folic acid vitamin D vitamin B12. B Evaluation for osteoporosis: obtain DEXA in patients at high risk of osteoporosis. B Show 2 more 3. Diagnostic procedures Upper gastrointestinal endoscopy: As per AGA 2019 guidelines, consider performing upper gastrointestinal endoscopy for differential diagnosis in adult patients with high levels (> 10 times the ULN) of anti- transglutaminase IgA and positive endomysial antibodies. E As per ACG 2013 guidelines: Perform upper gastrointestinal endoscopy with small-bowel biopsy as a critical component of the diagnostic evaluation in patients with suspected CD and to confirm the diagnosis. A Pursue intestinal biopsy even if serologies are negative in patients with highly suspected CD. B Video capsule endoscopy: As per ESGE 2023 guidelines: https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 6/15 6/29/23, 3:46 AM Celiac disease Pathway Perform small bowel capsule endoscopy only in cases of equivocal diagnosis of CD. B Perform small-bowel capsule endoscopy followed by device-assisted enteroscopy for diagnosis and monitoring in patients with nonresponsive or refractory CD. A As per ESsCD 2019 guidelines: Do not perform video capsule endoscopy for the initial diagnosis of CD, except in patients with positive CD-specific serology unwilling or unable to undergo endoscopy with biopsy. D Perform video capsule endoscopy for the detection of CD-associated complications. B As per ACG 2013 guidelines, avoid performing capsule endoscopy for initial diagnosis of CD, except in patients with positive CD-specific serology unwilling or unable to undergo upper endoscopy with biopsy. D Small bowel follow-through: do not perform small bowel follow-through studies for the diagnosis of CD, as it is neither specific nor sensitive. D Duodenal biopsy: As per ACG 2023 guidelines, perform EGD with multiple duodenal biopsies for confirmation of diagnosis in adult patients with suspected CD. B As per AGA 2020 guidelines: Perform a duodenal biopsy and analyze results at the time of serologic testing to determine exposure to gluten and the accuracy of test results. B Review histologic findings with experienced pathologists specialized in gastroenterology. B As per AGA 2019 guidelines, consider performing a duodenal biopsy for differential diagnosis in adult patients with high levels (> 10 times the ULN) of anti-transglutaminase IgA and positive endomysial antibodies. E Show 2 more As per ESsCD 2019 guidelines, perform a duodenal biopsy to confirm the diagnosis in adult patients with suspected CD. A Show 8 more 4. Medical management Goals of treatment: consider setting a goal of intestinal healing as an endpoint of gluten-free diet therapy. Provide an individualized discussion of goals of the gluten-free diet with the patient beyond clinical and serological remission. C Management of seronegative celiac disease: Treat seronegative patients with an identified cause for enteropathy accordingly. Consider performing a follow-up biopsy as necessary. B Initiate budesonide in patients with persistent signs and symptoms not responding to a gluten- free diet if no etiology of enteropathy is ultimately identified. B https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 7/15 6/29/23, 3:46 AM Celiac disease Pathway 5. Nonpharmacologic interventions Gluten-free diet (before the diagnosis): Discourage reduction or avoidance of gluten intake before diagnostic testing, as it may reduce the sensitivity of both serologic testing and biopsy. E Consider offering patients already following a gluten-free diet before the diagnosis to go back on a normal diet with 3 slices of wheat bread daily, preferably for 1- 3 months, before obtaining repeated anti-tissue transglutaminase IgA. E Gluten-free diet, after the diagnosis: As per ACG 2023 guidelines, advise consuming gluten-free oats in patients with CD. Monitor for oat tolerance because of gluten contamination of oats, variable toxicity in different varieties of oats, and the small risk for an immune reaction to the oat protein avenin. B As per ESsCD 2019 guidelines, advise adhering to a lifelong gluten-free diet in patients with CD. A Show 5 more As per ACG 2013 guidelines: Advise patients with CD to adhere to a gluten-free diet for life. Gluten-containing foods include wheat, rye, barley, and malt. A Refer patients with CD to a dietitian experienced in the management of CD to obtain a thorough review of the patient's diet. A Probiotics: insufficient evidence to recommend for or against the use of probiotics for the treatment of CD. I 6. Specific circumstances Pediatric and adolescent patients: As per ACG 2023 guidelines, perform EGD with multiple duodenal biopsies for confirmation of diagnosis in pediatric patients with suspected CD. B Show 3 more As per ESPGHAN 2020 guidelines, consider obtaining testing for CD in pediatric and adolescent patients with the following signs, symptoms, and conditions: Situation Guidance Chronic constipation not responding to usual treatment Gastrointestinal Chronic abdominal pain Distended abdomen Recurrent nausea Recurrent vomiting https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 8/15 6/29/23, 3:46 AM Celiac disease Pathway Extraintestinal Weight loss Failure-to-thrive Stunted growth/short stature Delayed puberty Amenorrhea Irritability Chronic fatigue Neuropathy Arthritis/arthralgia Chronic iron-deficiency anemia Decreased bone mineralization (osteopenia/osteoporosis) Repetitive fractures Recurrent aphthous stomatitis Dermatitis herpetiformis-type rash Dental enamel defects Abnormal liver biochemistry First-degree relatives with CD Specific conditions Autoimmune conditions (T1DM, thyroid disease, liver disease) Down syndrome Turner syndrome Williams-Beuren syndrome IgA deficiency. C Show 13 more As per ESsCD 2019 guidelines, confirm the diagnosis of CD based on a combination of clinical data, positive serology and duodenal biopsy in selected pediatric patients. B Show 6 more Patients with obesity: screen for nutritional status (malnutrition, sarcopenia, micronutrient deficiency, overweight, obesity) at the time of diagnosis and thereafter regularly (at least once a year) in patients with CD. B Show 5 more Patients with Helicobacter pylori infection: Consider obtaining serology or performing concomitant gastric biopsies when H. pylori infection is suspected. B Recognize that H. pylori infection is frequently associated with Marsh 1 histology and its eradication may lead to normalization of duodenal intraepithelial lymphocyte count. A https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 9/15 6/29/23, 3:46 AM Celiac disease Pathway Patients with non-celiac gluten sensitivity: suspect the diagnosis of non-celiac gluten sensitivity in patients with gluten-related intestinal and/or extra-intestinal complaints showing negative results for CD and positive wheat allergy serological markers on a gluten-containing diet. B Show 3 more Patients with enteropathy-associated T cell lymphoma: exclude the diagnosis of enteropathy- associated T-cell lymphoma in patients with CD having abdominal pain, fever, obstruction, anemia, gastrointestinal bleeding, or unexplained weight loss. B Show 2 more Patients with dermatitis herpetiformis: confirm the diagnosis of dermatitis herpetiformis by DIF examination of perilesional skin showing granular IgA deposits in the papillary dermis. A Show 4 more 7. Patient education Gluten detection devices: advise avoiding the routine use of gluten detection devices in food or biospecimens in patients with CD. B 8. Preventative measures Pneumococcal vaccination: As per ACG 2023 guidelines, consider offering vaccination to prevent pneumococcal disease in patients with CD. C As per ESsCD 2019 guidelines, offer pneumococcal vaccination in hyposplenic patients with CD. B 9. Follow-up and surveillance Follow-up, general principles: As per ESsCD 2019 guidelines: Obtain periodic follow-up by a gastroenterologist or physician with special expertise in CD. B Obtain regular monitoring for persistent or new symptoms, adherence to gluten-free diet and assessment for complications in patients with CD. B As per ACG 2013 guidelines: Monitor patients with CD regularly for residual or new symptoms, adherence to gluten-free diet, and assessment for complications; pay special attention to assure normal growth and development in children. B Obtain periodic follow-up by a healthcare practitioner with knowledge of CD. Offer consultation with a dietitian if gluten contamination is suspected. B Follow-up, monitoring for adherence: https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 10/15 6/29/23, 3:46 AM Celiac disease Pathway As per ESsCD 2019 guidelines: Obtain regular monitoring for adherence to gluten-free diet in patients with CD. B Obtain monitoring for adherence to gluten-free diet based on a combination of history and serology. Consider obtaining serum intestinal fatty acid binding protein to identify dietary non- adherence and unintentional gluten intake. B As per ACG 2013 guidelines, monitor adherence to the gluten-free diet based on a combination of history and serology (anti-transglutaminase or anti-gliadin antibodies). B Follow-up, serologic testing: As per AGA 2019 guidelines: Obtain follow-up serology 6 and 12 months after the diagnosis of CD, and yearly thereafter. E Recognize that celiac serology has a role in the detection of continued intestinal injury, particularly positive serology usually indicates ongoing intestinal damage and gluten exposure, while negative serology in a treated patient does not guarantee that the intestinal mucosa has healed. E As per ESsCD 2019 guidelines, consider obtaining repeated serologic testing at 3-6 months in asymptomatic patients with positive (but low titer) CD-specific serology to decide on performing biopsy. C Show 3 more As per ACG 2013 guidelines, ensure normalization of laboratory abnormalities detected during initial laboratory investigation as part of the ongoing monitoring of patients with CD. B Follow-up (dual-energy X-ray absorptiometry): obtain repeated DEXA at 5-years intervals in patients without malabsorption, absence of clinical presentation suggestive of bone disease, or not at high risk. Consider shortening intervals to 2-3 years in patients with low bone density on index measurement, evidence of ongoing villous atrophy or poor dietary adherence. B Management of refractory disease: As per AGA 2022 guidelines, review prior diagnostic testing, including serologies, endoscopies, and histologic findings, to conform the initial diagnosis of CD in patients with persistent or recurrent symptoms or signs. B Show 10 more As per AGA 2019 guidelines, perform endoscopic biopsies to determine healing in patients with persistent or relapsing symptoms without other obvious explanations for the symptoms, even in the presence of negative anti-tissue transglutaminase IgA. E As per ESsCD 2019 guidelines, obtain careful evaluation including the following to exclude dietary inconsistencies and identify other specific etiologies in patients showing slow response: review of initial diagnosis CD-specific serology dietary review follow-up duodenal biopsy. A Show 4 more https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 11/15 6/29/23, 3:46 AM Celiac disease Pathway As per ACG 2013 guidelines, differentiate between type 1 (normal intraepithelial lymphocyte phenotype), and type 2 (presence of abnormal intraepithelial lymphocyte phenotype) refractory CD, as this is important for management and prognosis. B Show 6 more Transition from pediatric to adult care: ensure a gradual transfer of medical care of adolescent patients with CD to adult care. Structure the transfer and include as the minimum written information on the base of diagnosis, follow-up, anthropometric data, comorbidities and dietary adherence. 10. Quality improvement Labelling regulations: Recognize the following regulations on gluten-free diets in Europe: gluten-free labels guarantee safety for consumers with dermatitis herpetiformis and CD foods labeled as "very low gluten content" are not suitable for consumers with dermatitis herpetiformis and CD hidden gluten contamination should be avoided as it is easy to reach toxicity thresholds. Clinical findings Symptoms Past medical history Abdominal pain Depression Amenorrhea Gluten-sensitive enteropathy Anxiety Iron deficiency anemia Bloating Osteoporosis Chronic diarrhea Family history Constipation Diarrhea Genetic predispositions Fatigue Neurological exam Flatulence Headache Cognitive impairment Itching Neuropathy Joint pain Limb numbness Musculoskeletal exam Loss of appetite Arthritis Loss of balance Malabsorption Hematological findings Nausea Skin rash Anemia Steatorrhea Hyposplenism Vomiting Imaging findings Weight loss https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 12/15 6/29/23, 3:46 AM Celiac disease Pathway Osteopenia Past obstetric history Early menopause Histological findings Late menarche Findings of celiac disease Anthropomorphic exam Delayed puberty Failure to thrive Malnutrition Abdominal exam Abdominal distension Lab findings serum ALT serum AST Serological findings anti-gliadin antibodies anti-tissue transglutaminase antiendomysial antibody Genetic testing Hla-dq2/dq8 Diagnostic procedures schilling test Likelihood Ratios Pertinent positives The following findings increase the probability of celiac disease in adults. 17 18 19 20 Finding LR+ Value Presence of findings of celiac disease* 89 Positive antiendomysial antibody 45 Positive anti-tissue transglutaminase 15.83 Presence of HLA-DQ2/DQ8 2.2 biopsy may be nondiagnostic in up to 10% of cases due to unacceptable quality Pertinent negatives https://web.pathway.md/diseases/recgzFTCzsFyHG1pf 13/15 6/29/23, 3:46 AM Celiac disease Pathway The following findings decrease the probability of celiac disease in adults. 17 18 19 20 Finding LR- Value Absence of HLA-DQ2/DQ8 0.04 Negative anti-tissue transglutaminase 0.05 Negative antiendomysial antibody 0.1 Absence of findings of celiac disease* 0.1 biopsy may be nondiagnostic in up to 10% of cases due to unacceptable quality References 1. Alberto Rubio-Tapia, Ivor D Hill, Carol Semrad et al. American College of Gastroenterology Guidelines Update: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2023 Jan 1;118 1 59 76. Open 2. Abdulbaqi Al-Toma, Umberto Volta, Renata Auricchio et al. European Society for the Study of Coeliac Disease ESsCD guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J. 2019 Jun;7 5 583 613. Open 3. Rubio-Tapia A, Hill ID, Kelly CP et al. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2013 May;108 5 656 76;. Open 4. Maureen M Leonard, Benjamin Lebwohl, Alberto Rubio-Tapia et al. AGA Clinical Practice Update on the Evaluation and Management of Seronegative Enteropathies: Expert Review. Gastroenterology. 2021 Jan;160 1 437 444. Open 5. Steffen Husby, Sibylle Koletzko, Ilma Korponay-Szab et al. 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