AmericanCollegeofGastroenterologyGuidelines

AmericanCollegeofGastroenterologyGuidelines

Update:DiagnosisandManagementofCeliacDisease

Alberto Rubio-Tapia, MD 1 , Ivor D. Hill, MD 2 , Carol Semrad, MD 3 , Ciar´an P. Kelly, MD 4 , Katarina B. Greer, MD, MS 5 , Berkeley N. Limketkai, MD, PhD, FACG 6 and Benjamin Lebwohl, MD, MS 7 This guideline presents an update to the 2013 American College of Gastroenterology Guideline on the Diagnosis and Management of Celiac Disease with updated recommendations for the evaluation and management of patients with celiac disease (CD). CD is defined as a permanent immune-mediated response to gluten present in wheat, barley, and rye. CD has a wide spectrum of clinical manifestations that resemble a multisystemic disorder rather than an isolated intestinal disease, and is characterized by small bowel injury and the presence of specific antibodies. Detection of CD-specific antibodies (e.g., tissue transglutaminase) in the serum is very helpful for the initial screening of patients with suspicion of CD. Intestinal biopsy is required in most patients to confirm the diagnosis. A nonbiopsy strategy for the diagnosis of CD in selected children is suggested and discussed in detail. Current treatment for CD requires strict adherence to a gluten-free diet (GFD) and lifelong medical follow-up. Most patients have excellent clinical response to a GFD. Nonresponsive CD is defined by persistent or recurrent symptoms despite being on a GFD. These patients require a systematic workup to rule out specific conditions that may cause persistent or recurrent symptoms, especially unintentional gluten contamination. Refractory CD is a rare cause of nonresponsive CD often associated with poor prognosis.

SUPPLEMENTARY MATERIALaccompanies this paper athttp://links.lww.com/AJG/C755

Am J Gastroenterol 2023;118:59–76. https://doi.org/10.14309/ajg.0000000000002075; published online September 21, 2022

INTRODUCTION

Guiding principles This document presents official recommendations from the American College of Gastroenterology (ACG) on the diagnosis, management, and follow-up of celiac disease (CD) in children and adults. This guideline was developed in compliance with the Institute of Medicine standards for practice guidelines and uses the Grading of Recommendation Assessment Development and Evaluation (GRADE) approach. The primary objective is to produce high-quality evidence-based clinical practice guidelines to answer common clinical questions and improve health care.The guideline evaluates a broad spectrum of clinical practice, including indication for CD testing; diagnostic strategies for in- dividuals on a gluten-containing diet or following a gluten-free diet (GFD); role of biopsy for confirmation of the diagnosis; in- dication for gluten challenge and genetic testing; general ap- proach to management; preventive care such as vaccination; monitoring of GFD adherence including discussion of gluten detection devices, probiotics, goals of therapy, and outcomes; and the differential diagnosis for nonresponsive CD.The guideline developers from ACG identified key questions that providers face frequently in the diagnosis, management, and follow-up of patients with CD (Tables 1 and 2). This guideline is intended for healthcare providers who care for patients with CD.Background

This guideline presents an update to the 2013 ACG Guidelines:

Diagnosis and Management of CD with updated recommenda- tions for the evaluation and management of patients with CD (1).CD affects nearly 1% of residents of the United States (2). CD is defined as a permanent immune-mediated response to gluten present in wheat, barley, and rye (3). CD has a wide spectrum of clinical manifestations that resemble a multisystemic disorder rather than an isolated intestinal disease. CD is characterized by small bowel injury and the presence of specific antibodies. De- tection of CD-specific antibodies (e.g., tissue transglutaminase [TTG]) in the serum is very helpful for the initial screening of patients with suspicion of CD. Intestinal biopsy is required in most patients to confirm the diagnosis. A nonbiopsy strategy for the diagnosis of CD in selected children is suggested and discussed in detail. Current treatment of CD requires strict adherence to a GFD and lifelong medical follow-up. Most patients have excellent clin- ical response to a GFD. Nonresponsive CD is defined by persistent or recurrent symptoms despite being on a GFD. These patients 1 Division of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA; 2 Division of Gastroenterology, Hepatology, and Nutrition, Nationwide Children Hospital, Columbus, Ohio, USA; 3 Division of Gastroenterology, University of Chicago, Chicago, Illinois, USA; 4 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; 5 Department of Medicine, Section of Gastroenterology and Hepatology, Louis Stokes VA Medical Center, Cleveland, Ohio, USA; 6 Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, California, USA; 7 Division of Gastroenterology and Hepatology, Columbia University, New York, USA.Correspondence:Alberto Rubio-Tapia, MD.

E-mail: RUBIOTA@ccf.org.

Received April 13, 2022; accepted August 23, 2022 © 2022 by The American College of GastroenterologyThe American Journal ofGASTROENTEROLOGY

CLINICAL GUIDELINES 59

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require a systematic workup to rule out specific conditions that may cause persistent or recurrent symptoms, especially un- intentional gluten contamination. Refractory CD (RCD) is a rare cause of nonresponsive CD often associated with poor prognosis.Epidemiology and burden of disease CD is common, with a point prevalence around 1% in most populations (3). The incidence of CD diagnosis has risen in recent decades (4), and this rise has been attributed to both increased awareness and testing (5) as well as a rise in autoimmunity; the latter has been demonstrated by seroprevalence studies of apparently asymptomatic individuals (6,7). Although earlier studies found that most patients with CD remain undiagnosed (2,5), this seems to have shifted in recent years (8).Measuring the burden of CD is limited by several factors, such as undiagnosed asymptomatic individuals and the fact that there are no prescription medications to treat the condition, which likely leads to undercoding. Although nearly 3 million Americans are estimated to have CD based on seroprevalence studies (2,5), an analysis of the National Ambulatory Medical Care Survey found only 190,381 office visits in 2014 associated with a di- agnosis code indicating CD (9). At the same time, disease burden Table 1.Questions and recommendations Question/recommendation Quality of evidence Strength of recommendation Dissent

• Should a combination of noninvasive serology tests vs duodenal biopsy be used to confirm the diagnosis of CD in children and adults?
• We recommend EGD with multiple duodenal biopsies for confirmation of

diagnosis in both children and adults with suspicion of CD Moderate Strong 1

• We suggest a combination of high-level TTG IgA (.103upper limit of normal)

with a positive EMA in a second blood sample as reliable tests for diagnosis of CD in children. In symptomatic adults unwilling or unable to undergo upper GI endoscopy, the same criteria may be considered after the fact, as a diagnosis of likely CD.Moderate Conditional 0

• Should intestinal mucosa healing vs clinical and serological remission be used as a goal of GFD therapy to improve long-term outcomes (5 yr or more) such as

mortality, cancer risk, and osteoporosis in adults with CD?We suggest setting a goal of intestinal healing as an end-point of GFD therapy. We advocate for individualized discussion of goals of the GFD with the patient beyond clinical and serological remission.Low Conditional 0

• Should gluten detection devices vs current standard of care be used to monitor adherence to GFD and/or patients’dietary decision-making?

We suggest against routine use of gluten detection devices in food or biospecimens among patients with CD.Low Conditional 1

• In patients with CD, what is the effect of probiotics in addition to GFD on the rates of clinical remission and mucosal healing compared with GFD alone?

There is insufficient evidence to recommend for or against the use of probiotics for the treatment of CD.Very low Evidence gap 1

• In patients with newly diagnosed CD, what is the effect of GFD without oats on increasing the rate of clinical remission and mucosal healing comparedwith GFD

with oats?We recommend consumption of gluten-free oats in the diet of those with CD.Gluten contamination of oats, variable toxicity in different varieties of oats, and the small risk for an immune reaction to the oat protein avenin requires monitoring for oat tolerance.Moderate Strong 0

• For patients with CD, does the use of pneumococcal vaccine reduce the future risk of serious pneumococcal infection compared with no pneumococcal

vaccine?We suggest vaccination to prevent pneumococcal disease in patients with CD Low Conditional 0

• Should case finding vs mass screening be used to improve detection of CD in the general population?
• We recommend case finding to increase detection of CD in clinical practice Low Strong 0
• We recommend against mass screening for CD in the community Low Strong 0
• Are TTG and DGP antibodies in combination more accurate in diagnosing CD in children younger than 2 yr compared with TTG alone?
• We recommend the immunoglobulin IgA anti-TTGA-IgA as the preferred single

test for detection of CD in children younger than 2 yr who are not IgA deficient Moderate Strong 0

• We recommend that testing for CD in children with IgA deficiency be performed

using IgG-based antibodies (DGP-IgG or TTG-IgG) Moderate Strong 0 CD, celiac disease; DGP, deamidated gliadin peptide; EMA, endomysial antibody; GFD, gluten-free diet; TTG, tissue transglutaminase.The American Journal ofGASTROENTEROLOGYVOLUME 118 | JANUARY 2023 www.amjgastro.com Rubio-Tapia et al.60 Copyright© 2022 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.Downloaded from http://journals.lww.com/ajg by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 06/01/2024 2 / 3

has been estimated as considerable based on economic analyses measuring the cost associated with outpatient care among pa- tients diagnosed with CD (10). This has been found to be par- ticularly increased in thefirst 2 years after diagnosis but has also increased in the years before diagnosis (11), presumably because of the development of symptoms that prompt investigation. In addition to the costs incurred by investigation of symptoms, di- agnosis, and monitoring, the increased cost of gluten-free foods compared with their gluten-containing counterparts is an im- portant component of disease burden (12). This cost is com- pounded by the noneconomic burden of the diet as reported by patients, whose rating of CD treatment burden is substantial (13).Methods of guideline development The process of guideline development is evidence-based, transparent, and systematic. Generation of recommendation involves both con- tent and methodology experts. The content experts determined the key clinical questions using the population/patient/problem, in- tervention, comparison, outcome (PICO) format, identified related literature and provided content expertise for interpretation of evi- dence, and constructed the manuscript with key concepts and rec- ommendations. Two experienced methodologists assessed the level of evidence using the GRADE framework and facilitated and guided discussion surrounding evidence and strength of recommendation.Technical remarks or key concepts are added to recommendations to help reconcile the level of the recommendation with the quality of the evidence and to facilitate implementation (Table 3).

GRADE SYSTEM

The strength of evidence is expressed as high (further research is very unlikely to change our confidence in the estimate of effect), moderate (further research is likely to have an important impact on our confi- dence in the estimate of effect and may change the estimate), low (further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate), or very low (any estimate of effect is very uncertain). The strength of the recommendation is expressed as strong or weak (it is permissible to use“conditional”or“discretionary”in place of the term“weak”).The guidelines, in addition to grading strength of evidence and strength of recommendation, will allow for dissent from the ma- jority opinion by one or more authors. This will simply be recorded by 0 dissent, 1 dissent, etc.These guidelines are established to support clinical practice and suggest preferable approaches to a typical patient with a particular medical problem based on the currently available published literature. When exercising clinical judgment, partic- ularly when treatments pose significant risks, healthcare providers should incorporate this guideline in addition to patient-specific medical comorbidities, health status, and preferences to arrive at a patient-centered care approach.Diagnosis

• Should a combination of noninvasive serology tests vs duodenal

biopsy be used to confirm the diagnosis of CD in children and adults?Recommendations 1A. We recommend EGD with multiple duodenal biopsies for confirmation of diagnosis in both children and adults with suspicion of CD (strong recommendation, moderate quality of evidence; dissent 1).1B. We suggest a combination of high-level TTG IgA (.103upper limit of normal) with a positive endomysial antibody (EMA) in a second blood sample as reliable tests for diagnosis of CD in children. In symptomatic adults unwilling or unable to undergo upper GI endoscopy, the same criteria may be considered after the fact, as a diagnosis of likely CD (conditional recommendation, moderate quality of evidence; dissent 0).Key concepts

• Multiple biopsies of the duodenum (1 or 2 from bulb and 4 from

distal duodenum) are necessary for diagnosis of CD.

• EGD and duodenal biopsies can also be useful for the differential

diagnosis of other malabsorptive disorders or enteropathies.

• Lymphocytic duodenosis ($25 intraepithelial lymphocytes per

100 epithelial cells) in the absence of villous atrophy is not specific for CD, and other causes should be considered.Background Intestinal biopsy has been a central test to confirm the diagnosis of CD since the late 1950s (14). Traditionally, the diagnosis of CD

required 3 intestinal biopsies: a biopsy on a gluten-containing diet

Table 2.Summary of Clinical Questions Evaluated using the PICO format Question Population Intervention Comparison Outcome

• Children and adults with CD Duodenal biopsy Serology tests Diagnostic accuracy
• Adults with CD Mucosal healing Clinical/serological remission Mortality
• Patient with CD Use of gluten detection devices Standard of care

a Improve adherence to GFD or help dietary decision making

• Adults with CD Probiotic1GFD GFD alone Clinical remission/mucosal healing
• CD patients Oats No oats Clinical remission/mucosal healing
• Adults with CD Pneumococcal vaccine No pneumococcal vaccine Serious pneumococcal infections
• General population Case finding Mass screening Rate of detection of CD
• Children ,2 yr old TTG 1deamidated peptide antibodies TTG alone Diagnostic accuracy

CD, celiac disease; GFD, gluten-free diet; PICO, patient/population/problem, intervention, comparison, outcome; TTG, tissue transglutaminase.a

Definition: regular follow-up without the use of gluten detection devices.

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