CLINICAL GUIDELINES 59
American College of Gastroenterology Guidelines
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Update: Diagnosis and Management of Celiac Disease
Alberto Rubio-Tapia, MD1, Ivor D. Hill, MD2, Carol Semrad, MD3, Ciarán P. Kelly, MD4, Katarina B. Greer, MD, MS5,
Berkeley N. Limketkai, MD, PhD, FACG6 and Benjamin Lebwohl, MD, MS7
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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 MATERIAL accompanies this paper at http://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 follow-up of patients with CD (Tables 1 and 2). This guideline is
Guiding principles intended for healthcare providers who care for patients with CD.
This document presents official recommendations from the
American College of Gastroenterology (ACG) on the diagnosis, Background
management, and follow-up of celiac disease (CD) in children This guideline presents an update to the 2013 ACG Guidelines:
and adults. This guideline was developed in compliance with the Diagnosis and Management of CD with updated recommenda-
Institute of Medicine standards for practice guidelines and uses tions for the evaluation and management of patients with CD (1).
the Grading of Recommendation Assessment Development and CD affects nearly 1% of residents of the United States (2). CD is
Evaluation (GRADE) approach. The primary objective is to defined as a permanent immune-mediated response to gluten
produce high-quality evidence-based clinical practice guidelines present in wheat, barley, and rye (3). CD has a wide spectrum of
to answer common clinical questions and improve health care. clinical manifestations that resemble a multisystemic disorder
The guideline evaluates a broad spectrum of clinical practice, rather than an isolated intestinal disease. CD is characterized by
including indication for CD testing; diagnostic strategies for in- small bowel injury and the presence of specific antibodies. De-
dividuals on a gluten-containing diet or following a gluten-free tection of CD-specific antibodies (e.g., tissue transglutaminase
diet (GFD); role of biopsy for confirmation of the diagnosis; in- [TTG]) in the serum is very helpful for the initial screening of
dication for gluten challenge and genetic testing; general ap- patients with suspicion of CD. Intestinal biopsy is required in most
proach to management; preventive care such as vaccination; patients to confirm the diagnosis. A nonbiopsy strategy for the
monitoring of GFD adherence including discussion of gluten diagnosis of CD in selected children is suggested and discussed in
detection devices, probiotics, goals of therapy, and outcomes; and detail. Current treatment of CD requires strict adherence to a GFD
the differential diagnosis for nonresponsive CD. and lifelong medical follow-up. Most patients have excellent clin-
The guideline developers from ACG identified key questions ical response to a GFD. Nonresponsive CD is defined by persistent
that providers face frequently in the diagnosis, management, and 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; 2Division of
Gastroenterology, Hepatology, and Nutrition, Nationwide Children Hospital, Columbus, Ohio, USA; 3Division of Gastroenterology, University of Chicago, Chicago,
Illinois, USA; 4Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; 5Department of Medicine, Section of
Gastroenterology and Hepatology, Louis Stokes VA Medical Center, Cleveland, Ohio, USA; 6Division of Digestive Diseases, UCLA School of Medicine, Los Angeles,
California, USA; 7Division 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
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Copyright © 2022 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
, 60 Rubio-Tapia et al.
Table 1. Questions and recommendations
Quality of Strength of
Question/recommendation evidence recommendation Dissent
1. Should a combination of noninvasive serology tests vs duodenal biopsy be used to confirm the diagnosis of CD in children and adults?
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A. We recommend EGD with multiple duodenal biopsies for confirmation of Moderate Strong 1
diagnosis in both children and adults with suspicion of CD
B. We suggest a combination of high-level TTG IgA (.103 upper limit of normal) Moderate Conditional 0
with a positive EMA in a second blood sample as reliable tests for diagnosis of CD in
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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.
2. 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 Low Conditional 0
advocate for individualized discussion of goals of the GFD with the patient beyond
clinical and serological remission.
3. 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 Low Conditional 1
among patients with CD.
4. 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 Very low Evidence gap 1
the treatment of CD.
5. In patients with newly diagnosed CD, what is the effect of GFD without oats on increasing the rate of clinical remission and mucosal healing compared with GFD
with oats?
We recommend consumption of gluten-free oats in the diet of those with CD. Moderate Strong 0
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.
6. 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
7. Should case finding vs mass screening be used to improve detection of CD in the general population?
A. We recommend case finding to increase detection of CD in clinical practice Low Strong 0
B. We recommend against mass screening for CD in the community Low Strong 0
8. Are TTG and DGP antibodies in combination more accurate in diagnosing CD in children younger than 2 yr compared with TTG alone?
A. We recommend the immunoglobulin IgA anti-TTGA-IgA as the preferred single Moderate Strong 0
test for detection of CD in children younger than 2 yr who are not IgA deficient
B. We recommend that testing for CD in children with IgA deficiency be performed Moderate Strong 0
using IgG-based antibodies (DGP-IgG or TTG-IgG)
CD, celiac disease; DGP, deamidated gliadin peptide; EMA, endomysial antibody; GFD, gluten-free diet; TTG, tissue transglutaminase.
require a systematic workup to rule out specific conditions that apparently asymptomatic individuals (6,7). Although earlier
may cause persistent or recurrent symptoms, especially un- studies found that most patients with CD remain undiagnosed
intentional gluten contamination. Refractory CD (RCD) is a rare (2,5), this seems to have shifted in recent years (8).
cause of nonresponsive CD often associated with poor prognosis. Measuring the burden of CD is limited by several factors, such
as undiagnosed asymptomatic individuals and the fact that there
Epidemiology and burden of disease are no prescription medications to treat the condition, which
CD is common, with a point prevalence around 1% in most likely leads to undercoding. Although nearly 3 million Americans
populations (3). The incidence of CD diagnosis has risen in recent are estimated to have CD based on seroprevalence studies (2,5),
decades (4), and this rise has been attributed to both increased an analysis of the National Ambulatory Medical Care Survey
awareness and testing (5) as well as a rise in autoimmunity; the found only 190,381 office visits in 2014 associated with a di-
latter has been demonstrated by seroprevalence studies of agnosis code indicating CD (9). At the same time, disease burden
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, Celiac Disease Guidelines 61
Table 2. Summary of Clinical Questions Evaluated using the PICO format
Question Population Intervention Comparison Outcome
1 Children and adults with CD Duodenal biopsy Serology tests Diagnostic accuracy
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2 Adults with CD Mucosal healing Clinical/serological remission Mortality
a
3 Patient with CD Use of gluten detection devices Standard of care Improve adherence to GFD or help
dietary decision making
4 Adults with CD Probiotic 1 GFD GFD alone Clinical remission/mucosal healing
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5 CD patients Oats No oats Clinical remission/mucosal healing
6 Adults with CD Pneumococcal vaccine No pneumococcal vaccine Serious pneumococcal infections
7 General population Case finding Mass screening Rate of detection of CD
8 Children ,2 yr old TTG 1 deamidated 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.
has been estimated as considerable based on economic analyses These guidelines are established to support clinical practice
measuring the cost associated with outpatient care among pa- and suggest preferable approaches to a typical patient with a
tients diagnosed with CD (10). This has been found to be par- particular medical problem based on the currently available
ticularly increased in the first 2 years after diagnosis but has also published literature. When exercising clinical judgment, partic-
increased in the years before diagnosis (11), presumably because ularly when treatments pose significant risks, healthcare providers
of the development of symptoms that prompt investigation. In should incorporate this guideline in addition to patient-specific
addition to the costs incurred by investigation of symptoms, di- medical comorbidities, health status, and preferences to arrive at a
agnosis, and monitoring, the increased cost of gluten-free foods patient-centered care approach.
compared with their gluten-containing counterparts is an im-
portant component of disease burden (12). This cost is com- Diagnosis
pounded by the noneconomic burden of the diet as reported by
patients, whose rating of CD treatment burden is substantial (13). 1. Should a combination of noninvasive serology tests vs duodenal
biopsy be used to confirm the diagnosis of CD in children and
adults?
Methods of guideline development
The process of guideline development is evidence-based, transparent,
and systematic. Generation of recommendation involves both con- Recommendations
tent and methodology experts. The content experts determined the 1A. We recommend EGD with multiple duodenal biopsies for
key clinical questions using the population/patient/problem, in- confirmation of diagnosis in both children and adults with
tervention, comparison, outcome (PICO) format, identified related suspicion of CD (strong recommendation, moderate quality of
literature and provided content expertise for interpretation of evi- evidence; dissent 1).
dence, and constructed the manuscript with key concepts and rec- 1B. We suggest a combination of high-level TTG IgA (.103 upper
ommendations. Two experienced methodologists assessed the level of limit of normal) with a positive endomysial antibody (EMA) in a
evidence using the GRADE framework and facilitated and guided second blood sample as reliable tests for diagnosis of CD in
discussion surrounding evidence and strength of recommendation. children. In symptomatic adults unwilling or unable to undergo
upper GI endoscopy, the same criteria may be considered after
Technical remarks or key concepts are added to recommendations to
the fact, as a diagnosis of likely CD (conditional
help reconcile the level of the recommendation with the quality of the recommendation, moderate quality of evidence; dissent 0).
evidence and to facilitate implementation (Table 3).
Key concepts
GRADE SYSTEM
The strength of evidence is expressed as high (further research is very 1. Multiple biopsies of the duodenum (1 or 2 from bulb and 4 from
unlikely to change our confidence in the estimate of effect), moderate distal duodenum) are necessary for diagnosis of CD.
(further research is likely to have an important impact on our confi- 2. EGD and duodenal biopsies can also be useful for the differential
dence in the estimate of effect and may change the estimate), low diagnosis of other malabsorptive disorders or enteropathies.
(further research is very likely to have an important impact on our 3. Lymphocytic duodenosis ($25 intraepithelial lymphocytes per
confidence in the estimate of effect and is likely to change the estimate), 100 epithelial cells) in the absence of villous atrophy is not specific
for CD, and other causes should be considered.
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 Background
strength of recommendation, will allow for dissent from the ma- Intestinal biopsy has been a central test to confirm the diagnosis of
jority opinion by one or more authors. This will simply be recorded CD since the late 1950s (14). Traditionally, the diagnosis of CD
by 0 dissent, 1 dissent, etc. required 3 intestinal biopsies: a biopsy on a gluten-containing diet
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