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,
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Berkeley N. Limketkai, MD, PhD, FACG6 and Benjamin Lebwohl, MD, MS7

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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 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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 62 Rubio-Tapia et al.

Table 3. Key concepts

Recommendation 1A and 1B
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.
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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
Recommendation 2
Upper endoscopy with intestinal biopsies is helpful for monitoring in cases with a lack of clinical response or relapse of symptoms despite a GFD
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Follow-up biopsy could be considered for the assessment of mucosal healing in adults in the absence of symptoms after 2 yr of starting a GFD after shared
decision-making between patient and provider
Recommendation 3
The standard of care in assessing diet adherence involves an interview with a dietitian with expertise in the GFD
Technologies to qualitatively detect gluten in food or biospecimens may not distinguish between clinically significant and trivial gluten exposure
There is a paucity of evidence to suggest that using gluten detection technology enhances diet adherence or quality of life.
Studies are needed to evaluate the utility of gluten detection technologies to improve GFD adherence and clinical outcomes in CD.
Recommendation 4
Dysbiosis is a feature of CD, but its role in disease pathogenesis and symptomatology is uncertain.
Despite the widespread use of probiotics, a benefit in the management of CD is not established.
Recommendation 5
Oat consumption seems to be safe for most individuals with CD, but may be immunogenic in a subset of patients.
Heterogeneity in the tolerance of oats may be related to differences in the origin/harvesting and quantity of oats consumed.
Intervals for monitoring symptoms and serology after gluten-free oats are introduced into the diet are not known.
Recommendation 6
Vaccination against pneumococcal infection is safe and effective.
Vaccination is widely recommended for all adults older than 65 yr and smokers aged 19–64 yr or adults with certain underlying conditions.
Recommendations 7A and 7B
Patients with symptoms, signs, or laboratory evidence suggestive of malabsorption, such as chronic diarrhea with weight loss, steatorrhea, abdominal pain, and
bloating, should be tested for CD.
Patients with symptoms, signs, or laboratory evidence for which CD is a treatable cause should be considered for testing for CD.
Patients with a first-degree family member who has a confirmed diagnosis of CD should be tested if they show possible signs, symptoms or laboratory evidence of CD.
Consider testing of asymptomatic relatives with a first-degree family member who has a confirmed diagnosis of CD.
Recommendations 8A and 8B
TTG-IgA and EMA-IgA are reported to be less accurate in children younger than 2 yr.
Current guidelines recommend that testing for CD in children younger than 2 yr include both TTG-IgA and DGP-IgG.

CD, celiac disease; DGP, deamidated gliadin peptide; EGD, esophagogastroduodenoscopy; EMA, endomysium antibodies; GFD, gluten-free diet; TTG, tissue
transglutaminase.

(diagnosis), a biopsy after a period on GFD (to demonstrate im- manifestations (6,18). A positive serological test is supportive of
provement), and a biopsy after a gluten challenge (to demonstrate the diagnosis but no single test is 100% specific for CD, and the
worsening) (15). Later studies demonstrated that a biopsy at the diagnostic accuracy varies considerably between laboratories
time of diagnosis in children without additional intestinal biopsies (19). Indeed, a large international study found that laboratory
was able to correctly diagnose 95% of cases (16). Thus, intestinal sensitivity ranged from 63% to 93%, and specificity ranged from
biopsy for confirmation of the diagnosis became standard of care. 96% to 100% when comparing TTG assays among various
More recently, in view of the excellent specificity of TTG antibodies research and clinical laboratories (20). Serological tests may
at high titters, a nonbiopsy diagnosis for selected children with perform less well in the clinical setting than research (a positive
suspicion of CD has been proposed (17). result of both TTG and EMA antibodies had a sensitivity of
81% in 1 study) (21). A diagnosis of CD is definitively confirmed
Evidence and rationale by the demonstration of histological changes associated with the
The availability of CD-specific serological tests facilitated the disease as classified according to Marsh or more recently the
recognition of patients with CD and the wide spectrum of clinical simplified Corazza classification (22,23) (see Supplementary

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 Celiac Disease Guidelines 63

Table 1, http://links.lww.com/AJG/C755). Small bowel biopsy is deficiency is present, then an IgG serology (commonly deami-
also useful for the differential diagnosis of other enteropathies or dated gliadin peptide [DGP] and/or TTG) should be measured.
malabsorptive disorders (24–27). The role of DGP IgG testing in IgA-deficient patients with
The diagnostic approach to CD for adults incorporates se- negative TTG IgG remains uncertain. Although a small proportion
rologic and histologic data and has not changed since the pub- of patients with CD have isolated elevations of this antibody (28),
lication of the last version of the ACG Guidelines (1). Testing the low positive predictive value has precluded its inclusion into
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should be considered in patients with signs or symptoms sug- diagnostic algorithms. Despite consistent reports of high specificity
gestive of CD, including diarrhea, weight loss, abdominal pain of EMA (19), given the limited availability and operator de-
and bloating, or laboratory abnormalities such as unexplained pendence of this assay, it is not included in the diagnostic algorithm
elevated serum aminotransferase levels. Testing of asymptom- for CD evaluation, outside of its use as a confirmatory test in
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atic individuals in populations at higher risk of CD can be children candidates for a nonbiopsy diagnostic algorithm (17).
considered (see Section 8). This algorithm (Figure 1), previously applicable to adults and
Serologic testing for CD should consist of measuring TTG IgA children $2 years, can now be applied to adults and children at any
while on a regular (gluten-containing) diet and, if the patient has age, as long as the individual undergoing testing is maintaining a
not previously been tested for IgA deficiency, concurrent mea- regular (gluten-containing) diet. Special considerations for indi-
surement of total IgA (Figure 1). Patients with an elevated TTG viduals following a GFD are also highlighted in the figure (for
IgA level should proceed to EGD with duodenal biopsy. Some further explication of serologic testing in pediatric populations, see
Section 9).
patients undergo EGD for the investigation of gastrointestinal
Symptomatic patients whose pretest suspicion for CD is high
symptoms before serology testing with either endoscopic findings
(.5%) should undergo upper gastrointestinal endoscopy with
of CD leading to duodenal biopsies or routine duodenal biopsies duodenal biopsy irrespective of serologic results, given the im-
with a subsequent finding of villous atrophy. In these patients, perfect sensitivity of serology, risk of verification bias on studies
checking a TTG IgA level is recommended to support the di- assessing CD testing, the possibility of seronegative CD, and dif-
agnosis of CD before starting a GFD. A negative TTG IgA in ferential diagnosis with other enteropathies (25,29).
patients without IgA deficiency has a high negative predictive Genetic testing for CD-compatible human leukocyte antigen
value if the pretest probability is low or moderate (19), and CD (HLA) haplotype is not required for diagnosis in all cases but may
can be considered adequately ruled out in this scenario. In pa- be helpful in selected situations such as in the context of serology-
tients with high pretest probability, EGD with duodenal biopsy histology discrepancy (1,3,25). If negative, CD is ruled out. HLA
should be considered even with a negative serology. If IgA testing is also central to the approach to CD testing for individuals

Figure 1. CD diagnostic testing algorithm. (1) Nonbiopsy criteria in children requires high-level TTG IgA (.103 upper limit of normal) with a positive EMA in a
second blood sample in children only if family agrees with no-biopsy strategy. (2) Duodenum sampling recommended: 1 or 2 biopsies from bulb and 4 biopsies
from distal duodenum. CD, celiac disease; CVID, common variable immune deficiency; DGP, deamidated gliadin peptide; EMA, endomysial antibody; HLA,
human leukocyte antigen; IgA, immunoglobulin A; IgG, immunoglobulin G; TTGA, tissue transglutaminase antibody.

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 64 Rubio-Tapia et al.

who have already started a GFD before evaluation; in the presence children has been adopted in Europe since 2012 and updated
of a CD-compatible haplotype, a gluten challenge can be offered. ESPGHAN guidelines in 2020 proposed that (i) HLA testing is no
Histological abnormalities associated with CD can be patchy longer necessary and (ii) a biopsy-free approach for asymptomatic
(30). Multiple biopsies of duodenum should be performed if the children (using the same criteria) is conditionally recommended
diagnosis of CD is considered, irrespective of the clinical pre- (17). A nonbiopsy diagnosis requires that the family agrees with
sentation. Among 132,352 patients without known CD who this approach. Given the high positive predictive value of serology
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underwent duodenal biopsy in the United States, the probability and the European experience of a biopsy-free approach for
of a new diagnosis of CD was significantly increased when $4 symptomatic children, this approach is a reasonable alternative to
specimens were submitted (1.8% vs 0.7%, P , 0.0001) as com- the standard approach to a CD diagnosis in selected children. One
pared with less than 4 (31). Unfortunately, 4 or more biopsies limitation of this approach includes the absence of standardization
were obtained in only 39% of patients who underwent biopsy of TTG assays and the real risk of misdiagnosis without following
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because of clinical suspicion of CD (31). In 1 study, the rate of the strict criteria proposed by ESPGHAN in clinical practice. In
duodenal biopsy was significantly lower among Black, older addition, the use of a predefined threshold to select a population to
($70 years), and male patients (32). In children and adults with avoid intestinal biopsy may not be the optimal strategy, although
positive CD-specific serology, adding biopsies of the duodenal emerging evidence suggests that a nonbiopsy diagnosis may be
bulb increases the diagnostic yield of CD (e.g., 9%–13% had accurate with different commercial serology kits and pretest
villous atrophy in the bulb alone) (33). In 1 study, a targeted probabilities (44,48,49). Unfortunately, solid information about
duodenal bulb biopsy from either the 9-o’clock or 12-o’clock nonbiopsy diagnosis of CD in the United States is not available yet.
position in addition to biopsies of distal duodenum had a sen- The primary concern about advocating a nonbiopsy approach for
sitivity of 96% for the diagnosis of CD (34). Care must be taken adults is the relative paucity of data regarding the positive predictive
when interpreting duodenal bulb biopsies to allow for the nor- value of serology in adults, as compared with the more extensive
mal surface architectural changes that overlie Brunner glands body of literature in children. One multicenter international study of
and the acute inflammatory changes of peptic duodenitis. It has adults found that a $10-fold elevation of TTG IgA had a positive
been recommended by expert opinion that only a single biopsy predictive value of 95% for CD (50). Given the life-long treatment
specimen should be obtained with each pass of the biopsy for- implications of a GFD, this may be unacceptably low. However,
ceps (35), based on the notion that specimen orientation may physicians may encounter clinical scenarios where a biopsy diagnosis
be improved (36). We recommend multiple biopsies of the may not be practical, such as a patient for whom an endoscopy and/
duodenum including 1 or 2 specimens from the bulb (either or biopsy poses a cardiovascular or bleeding risk. Moreover, some
9-o’clock or 12-o’clock position) and at least 4 biopsies of patients with highly elevated serology may have already started a
postbulbar duodenum. GFD before gastroenterology referral; among those who report a
Lymphocytic infiltration ($25 intraepithelial lymphocytes per severe symptomatic response to gluten exposure, a gluten challenge
100 epithelial cells) also known as lymphocytic duodenosis is followed by biopsy may not be advisable. As such, an “after-the-fact”
common in the general population (prevalence of 5.4%) and may be diagnosis of likely CD can be given to symptomatic adult patients
rising (37,38). Most patients with lymphocytic duodenosis do not with a $10-fold elevation of TTG IgA (a second confirmatory test
belong to the spectrum of CD; however, workup to rule out CD is such as EMA antibody is also advisable in adults). This diagnosis of
indicated (39,40). The frequency of diarrhea and weight loss was likely CD may be useful in research studies, including clinical trials
similar among patients with lymphocytic duodenosis and those for nondietary therapies, and, when considering candidacy for the
with CD (40). Anemia, skin disorders, positive TTG, and HLA DQ2 prescription of such therapies, should they be approved. Other po-
were more frequent among patients with CD (40). Other disorders tential benefits of nonbiopsy diagnosis in adults include reduction in
have been associated with lymphocytic duodenosis including Hel- the healthcare cost, avoidance of discomfort, and time lost from work
icobacter pylori infection, medications (e.g., nonsteroidal anti- for EGD.
inflammatory drugs), small bowel bacterial overgrowth, nonceliac
wheat/gluten sensitivity, and systemic autoimmune disorders.
Future research
Persistent intraepithelial lymphocytosis was observed in 56% pa-
tients with treated CD despite the evidence of normal villous ar- • Is there an optimal cutoff for serologic values that provides an
chitecture, and the only factor associated with this finding was oat acceptable positive predictive value for the diagnosis of CD in
consumption (41). Among 56 children without a prior diagnosis of adults across a range of commercial laboratories?
CD and lymphocytic duodenosis evaluated at a referral center, CD • Does the positive predictive value of serologies vary according to
was diagnosed in only 9% of these cases (42). A GFD may be con- the patient’s symptomatology and the coexistence of other
sidered in symptomatic children and adults with either lymphocytic autoimmune diseases?
duodenosis or Marsh II (lymphocytic duodenosis and crypt hy- • What are the downstream effects in clinical practice of offering a
perplasia without atrophy) lesions who have elevated CD-related nonbiopsy diagnosis strategy?
antibodies, especially EMA (43). • Does a nonbiopsy diagnosis have an effect on adherence to the
A guideline endorsed by the European Society of Pediatric GFD?
Gastroenterology, Hepatology, and Nutrition (ESPGHAN) pro-
posed that it may be possible to avoid any intestinal biopsy in
children who meet the following criteria: characteristic symptoms Diet and long-term outcomes
of CD, and TTG IgA levels .103 upper limit of normal (con- 2. Should intestinal mucosa healing vs clinical and serological
firmed with a positive EMA antibody in a different blood sample) remission be used as a goal of GFD therapy to improve long-term
(17). This is based on prospective data in children (and, to a lesser outcomes (5 years or more) such as mortality, cancer risk, and
degree, adults) (44–47). This nonbiopsy approach in symptomatic osteoporosis in adults with CD?

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 Celiac Disease Guidelines 65

Recommendation and development are achievable on a GFD and should be goals for
monitoring children with CD. Control of symptoms (if present),
2. We suggest setting a goal of intestinal healing as an end point of
GFD therapy. We advocate for individualized discussion of goals of facilitation of adherence to GFD, preventive care (e.g., vaccines,
the GFD with the patient beyond clinical and serological remission dual‐energy x‐ray absorptiometry [DXA]), monitoring of sero-
(conditional recommendation, low quality of evidence; dissent 0). conversion (e.g., going from positive to negative serology), active
surveillance of comorbidity (especially coexistent autoimmune
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Key concepts disease), and avoidance or early detection of complications should

be the general goals of monitoring after diagnosis of CD. Clinical
1. Upper endoscopy with intestinal biopsies is helpful for monitoring follow-up after diagnosis may require multiple visits during the first
in cases with a lack of clinical response or relapse of symptoms year after diagnosis (e.g., 3, 6, 12 months) and regular visits (e.g.,
despite a GFD.
twice a year or yearly) thereafter (Figure 2). A visit with a dietitian
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2. Follow-up biopsy could be considered for assessment of mucosal after diagnosis is mandatory, and subsequent visits as needed to
healing in adults in the absence of symptoms after 2 years of
reinforce GFD education and adherence should be encouraged.
starting a GFD after shared decision-making between patient and
provider. Although the rate of mucosal healing after adoption of a GFD is
variable (57), there is no question that this goal may be achievable
over time, especially with good adherence to the GFD. However, the
long-term benefit of active monitoring for mucosal healing after
Background
starting a GFD is controversial (58). In addition, there is poor
A GFD is the only effective therapy for CD (51). There are multiple correlation between serology and mucosal healing, and although a
benefits of strict adherence to the GFD (52). It is expected that negative celiac serology (seroconversion) increases the probability
symptoms improve within days of strict adherence to a GFD (e.g., of mucosal healing, correlation is not good enough and currently a
diarrhea improved in most patients [80%] within 60 days) (53). repeat intestinal biopsy is the only reliable method to assess for
Adherence to GFD is very effective in controlling a wide variety of mucosal healing (57).
symptoms and also reducing healthcare utilization (54). Experts
consistently agree on the necessity of long-term monitoring of
patients with CD. The number of patients with CD who receive Evidence and rationale
follow-up is unknown. In the United States, follow-up seems to be Intestinal biopsies are the only way to document mucosal healing
suboptimal in practice (55). A systematic review supports the role of of the intestine. Mucosal healing in CD after starting a GFD takes
strict adherence to the GFD to control symptoms, improve quality time and is incomplete or absent in a substantial number of pa-
of life, and decrease the risk of complications (56). Normal growth tients diagnosed during adult life. Indeed, in adults, the intestine

Figure 2. An approach to monitoring CD. (1) TTG and DGP can be used for monitoring CD considering the availability of test at baseline before initiation of
the GFD. (2) Other tests may include complete blood count, alanine aminotransferase, aspartate aminotransferase, vitamins (A, D, E, B12), copper, zinc,
folic acid, ferritin, and iron. (3) Blood tests at follow-up should be individualized to verify correction of laboratory tests that were abnormal at baseline. (4) The
role of biopsy for monitoring CD and to check for mucosal healing (suggested at year 2 following the GFD) is discussed in detail in the text. CD, celiac disease;
DGP, deamidated gliadin peptide; DXA, dual-energy x-ray absorptiometry; GFD, gluten-free diet; TTG, tissue transglutaminase.

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 66 Rubio-Tapia et al.

will often fail to heal despite negative serology and the absence of Recommendation
symptoms on a GFD (57). This lack of mucosal healing may be
3. We suggest against routine use of gluten detection devices in food
associated with increased risk of lymphoproliferative malig- or biospecimens among patients with CD (conditional
nancy (hazard ratio [HR] 5 2.81, 95% confidence interval [CI]: recommendation, low quality of evidence; dissent 1).
2.10–3.67) (59), bone disease specifically increased hip fracture
risk (HR 5 1.67; 95% CI: 1.05–2.66) (60), and ultimately a di- Key concepts
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agnosis of RCD in symptomatic patients with good adherence to

the GFD. A large Swedish study demonstrated a null risk of 1. The standard of care in assessing diet adherence involves
lymphoma (HR 5 0.97; 95% CI 5 0.44–2.14) among patients interview with a dietitian with expertise in GFD.
with normal follow-up histology, suggesting that mucosal 2. Technologies to qualitatively detect gluten in food or
healing could be a goal to consider during follow-up (61). biospecimens may not distinguish between clinically significant
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Among a group of 381 patients with baseline and follow-up and trivial gluten exposure.
biopsy after GFD, mucosal healing was associated with a bor- 3. There is a paucity of evidence to suggest that using gluten
derline lower risk of death (HR 5 0.13, 95% CI: 0.02–1.06, P 5 detection technology enhances diet adherence or quality of life.
0.06) adjusted for age and sex (57). A much larger study from 4. Studies are needed to evaluate the utility of gluten detection
Sweden failed to confirm a protective role of mucosal healing on technologies to improve GFD adherence and clinical outcomes
in CD.
mortality risk, yet mortality risk was significantly lower among
patients who underwent follow-up biopsy regardless of the re-
sult, compared with those who did not undergo a follow-up
biopsy likely related to the benefits of regular medical follow-up Background
(62). Moreover, mucosal healing does not influence the risk of In recent years, multiple commercially available tools have been
serious infection (HR 5 0.99, 95% CI: 0.88–1.11) (63), ischemic introduced that detect gluten in food and biospecimens. These
heart disease or atrial fibrillation (64), or adverse outcomes of measure gluten proteins, but because they do not directly diagnose
pregnancy such as intrauterine growth retardation, low birth or treat a medical condition, they are not subject to US Food and
weight, preterm birth, or cesarean section (65). The putative Drug Administration oversight. Evidence of their performance
benefits of follow-up biopsy are based on observational studies, characteristics has been published in the peer-reviewed literature,
and there are no prospective randomized trials of a follow-up and these tools are directly marketed to the public.
biopsy approach vs a no-follow-up biopsy approach. Therefore,
a personalized approach is required to decide monitoring of Evidence and rationale
mucosal healing with shared decision-making between the The concept of patient-directed testing for gluten dates back to
physician and the patient. 1991 (67) and subsequent commercially available kits largely for
In a US study, the median time from the onset of GFD to home use (Glutentox and EZ gluten) were developed (68,69). More
achieve mucosal healing in adults was 3 years (57). Accord- recently, the Nima sensor is a portable lateral flow gluten-sensor
ingly, it is reasonable to consider a follow-up biopsy in adults device that returns a “gluten found” or a “gluten-free” result for a
after 2 years of starting a GFD to assess for mucosal healing. pea-sized sample after approximately 3 minutes (70,71). The sen-
Mucosal healing was observed in 95% children within 2 years sitivity of Nima for gluten depends on concentration and is .98%
of starting a GFD (66). The consideration to perform follow- for food items .40 parts per million (ppm). However, this sensi-
up biopsy may be different in children because they have tivity does not take into account the limitation that Nima is unable
higher rates of mucosal healing on a GFD, and there are ad- to detect gluten in fermented form (e.g., in soy sauce or as barley
ditional inherent challenges for endoscopy in children that malt). Although purely gluten-free foods correctly tested negative
alter the risk-benefit ratio of this procedure. Currently, with the device .94% of the time, when foods were “spiked” with
follow-up biopsy in asymptomatic children following a GFD gluten that did not meet the threshold for 20 ppm (and are thus still
is not recommended. considered gluten-free), the device returned a “gluten found” more
than 50% of the time for items with 10–19 ppm of gluten. There-
fore, both false-positive and false-negative results are a significant
Future research
limitation. To date, there has been one published study measuring
• Does a strategy of follow-up biopsy in asymptomatic individuals outcomes of patients using the Nima sensor. That study, a 30-
with CD have an effect on adherence to the GFD and quality of life? subject pilot trial, found that adults (but not teenagers) given the
• Are there biomarkers (used alone or in combination) that can Nima sensor reported improved CD-related quality of life after 3
predict the presence of mucosal healing vs persistent villous months. Limitations of that study include the lack of a control arm
atrophy in treated CD? of standard of care (or a sham device) and the lack of objective
outcomes including villous histology. (72).
As other food-testing devices become available for people with
Medical device use CD (73–75), it is imperative that their validity be rigorously tested
and their impact on patient outcomes be studied. Even if perfor-
3. Should gluten detection devices vs current standard of care be mance characteristics improve, such as superior ability to discern at
used to monitor adherence to GFD and/or patients’ dietary the 20 ppm cutoff, there will be residual concern that sampling at
decision-making? the point of care (without homogenization) will be limited by the

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 Celiac Disease Guidelines 67

possible presence of gluten in an unsampled fragment of food. immunomodulators, mesalamine, and biologics, although
Thus, although this technology may prove useful for patients in placebo-controlled data are lacking (83). RCD type 2, characterized
select scenarios, the optimal setting and ultimate value of point-of- by a clonal T-cell population, has a poorer prognosis and is often a
care gluten detection remains uncertain. precursor to enteropathy-associated T-cell lymphoma (86). Open-
Because gluten is incompletely digested into peptide fragments capsule budesonide, cladribine, and autologous stem-cell trans-
by all individuals, these fragments are detectable in stool and urine, plantation are potential therapeutic options. Parenteral nutritional
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allowing for potential diagnostic use (76). Gluten fragments have support is often needed (83).
been detected in stool up to 4 days after ingestion (77) and in
urine for up to 2 days (78). Gluten in stool has been detected in Future research
nearly 30% of individuals with CD attempting to adhere to a
GFD, and their presence may be more sensitive than a dietary • What is the impact of the prescription of gluten detection
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questionnaire or TTG antibodies in identifying gluten exposure technology on adherence to the GFD, symptom control, and
(79). The presence of urinary gluten fragments is a stronger mucosal healing?
predictor of persistent villous atrophy on follow-up biopsy than • What is the optimal dietary counseling approach to patients who
elevated serology (78). adopt gluten detection technology?
Despite the potential promise of this technology, strategies • Does the presence of gluten in food or stool and urine in quantities
of incorporating biospecimen detection of gluten into clinical below traditionally regarded toxic doses result in clinically relevant
outcomes?
management have not been tested. Although there may be a role
for spot-checking for gluten exposure in select scenarios, it is
not given that this approach will improve adherence to the
GFD, quality of life, or other clinical outcomes. Furthermore, Probiotics
the clinical significance of these highly sensitive tests is un-
4. In patients with CD, what is the effect of probiotics in addition to
certain. Urine testing can detect as little as 25 mg of ingested
GFD on the rates of clinical remission and mucosal healing
gluten, which may be below the limit of toxicity for a substantial compared with GFD alone?
proportion of patients with CD (78). Patients with persistent
symptoms were actually less likely to have detectable gluten
Recommendation
fragments compared with asymptomatic patients, possibly
because of the fact that persistent symptoms (which are not 4. There is insufficient evidence to recommend for or against the use
necessarily due to gluten exposure) may spur further stringent of probiotics for the treatment of CD (evidence gap in
efforts to avoid cross-contact with gluten (80). Because the recommendation; very low quality of evidence; dissent 0).
patient perspective was not evaluated during guideline de-
velopment, we recognize that there may be subgroups of pa- Key concepts
tients with CD who find this type of novel technology valuable 1. Dysbiosis is a feature of CD, but its role in disease pathogenesis
and believe it may give them a better sense of control over their and symptomatology is uncertain.
disease. In the absence of certainty regarding whether to in- 2. Despite the widespread use of probiotics, a benefit in the
corporate gluten detection technology in the management of management of CD is not established.
CD, the evaluation of persistent or recurrent symptoms
should take into account previously identified etiologies (81).
This includes reviewing and confirming the initial diagnosis
of CD, evaluation for inadvertent gluten exposure (through Background
assessment by an expert dietitian and serology), assessment Advances in our understanding of the intestinal microbiome have
for a coexisting functional disorder, and selective testing led to great interest among patients about the potential to
(based on clinical suspicion) of food intolerances (e.g. lac- translate these advances into therapeutic strategies for gastroin-
tose, fructose), pancreatic insufficiency, microscopic colitis, testinal conditions. Probiotics, live microorganisms administered
and small intestinal bacterial overgrowth, among others (82) for therapeutic purposes, have been evaluated extensively in
(Figure 3). conditions such as Clostridioides difficile colitis (87) and
RCD refers to ongoing symptoms and/or signs of malab- antibiotic-associated diarrhea (88) in which there is a suggestion
sorption with intestinal villus atrophy despite the evidence of of a beneficial effect. By contrast, far fewer data exist regarding the
strict adherence to a GFD for at least 12 months (83). This is use of probiotics for the treatment of CD.
relatively rare outside of referral centers, comprising ,1% of
patients with CD (84). Central to the initial assessment is the Evidence and rationale
differentiation between RCD types 1 and 2 by assessment for The rationale for the use of probiotics stems from study findings
immunostains (CD3 and CD8), T-cell clonality through T-cell that a state of dysbiosis exists in the duodenal microbiome of
receptor polymerase chain reaction (PCR), and/or flow individuals with CD before and subsequent to the disease de-
cytometric analysis of duodenal biopsy specimens. RCD type velopment. Infants with a family history of CD who carry the
1, characterized by a polyclonal T-cell population, likely has a HLA DQ2 haplotype have higher proportions of certain gut
heterogeneous group of etiologies, including inadvertent microbial phyla (Firmicutes and Proteobacteria) compared with
gluten exposure; as such, it may be managed with further di- infants at low genetic risk (89). After diagnosis of CD and treat-
etary restriction, eliminating nearly all processed foods for a ment with a GFD, the feces of children on this diet have lower
defined period (85). Medications that have been used to treat counts of Lactobacillus species (90). Patients with ongoing gas-
RCD include open-capsule budesonide, prednisone, trointestinal symptoms despite healed villi may have a distinct

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Figure 3. An approach to the investigation of nonresponsive celiac disease (NRCD) and refractory celiac disease (RCD) (adapted from references Leffler et al.
(81) Rubio-Tapia et al. (82)). (1) NRCD may be defined as persistent symptoms, signs, or laboratory abnormalities typical of CD despite 6–12 months of dietary
gluten avoidance. (2) Causes of nonceliac, small-intestinal villous atrophy that may be misdiagnosed as CD include autoimmune enteropathy, tropical sprue,
small-intestinal bacterial overgrowth, hypogammaglobulinemia and combined variable immunodeficiency, collagenous sprue, eosinophilic enteritis, Crohn’s
disease, and peptic duodenitis. (3) Conditions that present clinically in a similar fashion to CD but where villous atrophy is not evident include irritable bowel
syndrome, food intolerances, small-intestinal bacterial overgrowth, eosinophilic enteritis, Crohn’s disease, and microscopic colitis. (4) Positive celiac serologies
despite 12 months of treatment with a GFD suggest that there may be ongoing gluten ingestion. (5) RCD may be defined as persistent or recurrent malabsorptive
symptoms and signs with small-intestinal villous atrophy despite a strict GFD for more than 12 months and in the absence of other disorders, including overt
lymphoma. (6) Abnormal intestinal lymphocytes may be identified by the immunohistochemistry of IELs or by flow cytometry showing an increased number of
CD3-positive cells lacking CD8, or by the identification of clonal T-cell receptor gene rearrangement by molecular analysis. CD, celiac disease; DGP, deamidated
gliadin peptide; EMA, endomysium antibodies; GFD, gluten-free diet; HLA, human leukocyte antigen; IELs, intraepithelial lymphocytes; TTGA, tissue trans-
glutaminase antibody.

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 Celiac Disease Guidelines 69

microbial signature in the duodenum compared with those whose Recommendation

symptoms have resolved (91,92).
5. We recommend consumption of gluten-free oats in the diet of
Administration of probiotics might restore the putative dys- those with CD. Gluten contamination of oats, variable toxicity in
biosis documented in CD. A pilot study of 40 children with CD different varieties of oats, and the small risk for an immune
administered a probiotic containing a combination of Bifido- reaction to the oat protein avenin require monitoring for oat
bacterium strains for 3 months resulted in a stool Firmicutes/ tolerance (strong recommendation, moderate quality of evidence;
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Bacteroidetes ratio that seemed more similar to controls after the dissent 0).
intervention (93). A double-blind, randomized, placebo-
controlled trial of a Bifidobacterium probiotic in 33 children
for 3 months found that those randomized to the probotic arm Key concepts
had a marginally greater increase in height percentile compared
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1. Oat consumption seems to be safe for most individuals with CD,

with the placebo group, without a difference in ongoing symp- but may be immunogenic in a subset of patients.
toms (94). 2. Heterogeneity in the tolerance of oats may be related to
Administration of probiotics at the outset of CD diagnosis has differences in the origin/harvesting and quantity of oats
been proposed as a potential therapeutic strategy and was tested consumed.
in a pilot randomized, double-blind, placebo-controlled trial of 22 3. Intervals for monitoring symptoms and serology after gluten-free
adults with elevated CD serologies who were still eating a gluten- oats are introduced into the diet are not known.
containing diet and had not yet undergone duodenal biopsy.
Compared with those randomized to placebo, those randomized
to the probiotic Bifidobacterium natren (Life Start) had a greater Background
improvement in gastrointestinal symptoms and lower levels of The addition of pure/uncontaminated oats to a GFD in people with
IgA antibodies to TTG and DGP (95). CD adds palatability, nutrition (soluble fiber, polyunsaturated oil, B
Because many patients with CD have ongoing symptoms vitamins, iron, thiamine), and laxation benefits. Variation in con-
that are attributed to functional disorders such as irritable tamination by gluten-containing grains in different varieties of oats
bowel syndrome (96), probiotics have been proposed to have a and their innate ability to trigger an immune reaction in vitro in
role in the treatment of these symptoms. In a randomized, some patients with CD confound interpretation of the literature on
double-blind, placebo-controlled trial of 109 adults with CD the safety of oats in patients following GFD (100).
and irritable bowel syndrome-type symptoms, a combination
probiotic consisting of Lactobacilli and Bifidobacteria for 6 Evidence and rationale
weeks was superior to placebo in achieving the primary end Given the distinct phylogenetic lineage of oats (avenae) from wheat,
point of an improvement of the irritable bowel syndrome se- rye, and barley (triticeae), oats have been believed to be non-
verity scoring system, although quality of life scores did not immunogenic in people with CD. However, there are conflicting re-
improve (97). ports as to the safety of oats in this population. Although some studies
Despite these promising pilot studies, there remain multiple show good tolerance to oats, even at high amounts in adults and
uncertainties about the role of probiotics in the treatment of CD. children (101–103), other studies show an increase in symptoms,
The clinical significance of the symptom responses found in the intraepithelial lymphocytosis, villous atrophy on rechallenge, and
above-cited trials was measured in the short term, and their du- avenin-specific T-cell inflammatory response (104–106). Whether
rability is not certain. The implications of longer-term probiotic studies that show intolerance to oats in the diet is due to increased fiber
administration raise concerns for safety, particularly given the fact causing GI symptoms, contaminated oats, or an immunologic reaction
that probiotics marketed as supplements have a lax regulatory to avenin in oats remains unknown. This has led to conflicting rec-
standard in the United States, with minimal safety data available ommendations regarding the use of oats in a GFD in people with CD.
before their introduction to the market. Indeed, there is concern In a recent systematic review and meta-analysis (107) of the
that some probiotics on the market contain detectable gluten, de- safety of oats in GFD in CD, 28 studies (661 patients, 6 randomized
spite being labeled gluten-free (98). The conventional wisdom of control trials, and 2 nonrandomized control trials) were included.
probiotics as a treatment of dysbiosis has also been questioned by a Oat consumption in GFD for 12 months showed no effect on
study that found that recovery from antibiotic-induced dysbiosis is symptoms, histologic scores, or serologic test results in both adults
actually delayed among individuals exposed to probotics (99). and children with CD. The quality of evidence was deemed low
because of the lack of type of origin and quantity of oats, variation
Future research in study design and time, small number of randomized controlled
• Do changes in the intestinal microbiome play a causal role in the trials, and lack of information on compliance with GFD.
development of CD? More recently, 2 studies have further supported the safety of pure/
• Does modification of the microbiome through orally administered uncontaminated oats in people with CD following GFD. A large,
probiotics result in improved clinical outcomes in CD? cross-sectional study (108) of patients with CD from Finland
reported that long-term consumption of oats was found to be safe
and improved quality of life. Of the 869 subjects in the study, 82% ate
Nutrition oats with a median duration of 10 years. Those who ate oats when
compared with those who did not eat oats showed no difference in
5. In patients with newly diagnosed CD, what is the effect of GFD dietary adherence to GFD, symptoms, positive EMA, histologic re-
without oats on rates of clinical remission and mucosal healing covery after 1 year, malignancy, bone disease, or fractures. Those
compared with a gluten-free diet with oats? who consumed oats had better health scores. A double-blind,

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 70 Rubio-Tapia et al.

randomized, cross-over, placebo-controlled trial of the safety of oats 2 years and all adults older than 65 years. Vaccination is also rec-
in children with CD (109) reported that pure oat products are safe in ommended for adults aged 19–64 years with certain underlying
the diet of children with CD. The study included 177 children conditions (e.g., smoker and others). Pneumococcal vaccine is both
(79 oats-placebo, 98 placebo-oats). The oat varieties used were safe and effective to decrease the burden of pneumococcal infection.
“Irina and Potenza” Avena sativa that lack in vitro immune The specific vaccination regimen depends on patient age, immuni-
reaction in patients with CD and was double checked for zation record, and comorbidity following CDC recommendations.
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contamination by using enzyme‐linked immunosorbent assay For example, in an adult patient with CD and functional asplenia
testing. The oat treatment effect was not statistically significant (a common clinical association in CD), CDC recommends for those
for clinical symptoms, serologic results (anti-TTG, anti- who have not previously received any pneumococcal vaccine
avenin), or intestinal permeability changes. or whose previous vaccination history is unknown to give 1
Based on past and recent studies, Finnish pure oats and the dose of PCV15 or PCV20: when PCV15 is used, this should be
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Avena sativa oat varieties are safe when added to GFDs of chil- followed by a dose of PPSV23 at least 1 year later, and if PCV20
dren and adults with CD. Given the variety of oats with variable is used, a dose of PPSV23 is not indicated. For adult patients
toxicity (110) and uncertainty as to whether oats stripped of with CD and no other conditions with specific vaccination
gluten contamination during harvesting are considered safe for recommendation by CDC, we suggest to give 1 dose of PCV20
all people with CD, patients require monitoring for tolerance alone or 1 dose of PCV15 first and then consider to give 1 dose
when pure/uncontaminated oats are added to GFD. This is in of PPSV23 at least 1 year later to maximize vaccine efficacy and
accordance with previous ACG 2013 CD guidelines to note that protection. For complex vaccination scenarios, a vaccination
pure/uncontaminated oats can safely be ingested by people with clinic or infectious disease specialist consultation whenever
CD, but that a small number may be intolerant of pure oats, and available is reasonable.
thus, they should be monitored for signs of clinical and serological
relapse (1).
Evidence and rationale
Adults with CD have a significantly increased risk of pneumo-
Future research
coccal infections (sepsis, pneumonia) (111–113). In a
• Does an initial oats-avoidant strategy after diagnosis of CD result in population-based study using a health registry in Italy, children
improved symptoms and healing rates? with CD were at increased risk of bacterial pneumonia com-
• What proportion of patients with CD mount an immune response to pared with reference individuals, particularly before diagnosis,
pure oats, and does this change over the course of the natural but pneumococcal infections were not significantly increased
history of CD? (114). The increased risk of pneumococcal infection is believed
• What is the incremental benefit, in terms of symptoms, intestinal to be due to hyposplenism (frequently subclinical) found in
healing, and quality of life, of recommended pure/uncontaminated approximately one-third of those with CD based on pitted red
oats vs any oats? cell counting (115,116). In one small study, people with CD were
capable of mounting antibody responses to a polyvalent pneu-
mococcal vaccine, but it is uncertain whether those vaccinated
Pneumococcal vaccine had hyposplenism (117). In a recent systematic review and
meta-analysis, CD was associated with an overall 2-fold in-
6. For patients with CD, does the use of pneumococcal vaccine
creased risk of pneumococcal infection when compared with
reduce the future risk of serious pneumococcal infection
compared with no pneumococcal vaccine?
patients and general population (118).

Recommendation Future research

6. We suggest vaccination to prevent pneumococcal disease in • What is the effectiveness of the pneumococcal vaccine among
patients with CD (conditional recommendation, low quality of patients with CD, and does this differ compared with the general
evidence; dissent 0). population?
• Does a strategy of vaccination against pneumococcal disease
Key concepts among patients with CD younger than 65 years lead to
reduced pneumococcal infection-related morbidity and
1. Vaccination against pneumococcal infection is safe and effective.
mortality?
2. Vaccination is widely recommended for all adults older than 65
• What is the best vaccination regimen for patients with CD?
years and smokers aged 19–64 years or adults with certain
underlying conditions.

Screening
Background
7. Should case finding vs mass screening be used to improve
Vaccination plays a critical role to decrease the burden of pneumo- detection of CD in the general population?
coccal infection. There are several available vaccines in the United
States as follows: pneumococcal conjugated vaccine (PCV13, Pre-
Recommendation
vnar13, Pfizer; PCV15, Vaxneuvance, Merck; and PCV20, Prevnar20,
Wyeth Pharmaceuticals, LLC) and pneumococcal polysaccharide 7A. We recommend case finding to increase detection of CD in
vaccine (PPSV23, Pneumovax, Merck). The Centers for Disease clinical practice (strong recommendation, low quality of
Control (CDC) recommend vaccination for all children younger than evidence; dissent 0).

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 Celiac Disease Guidelines 71

7B. We recommend against mass screening for CD in the Table 4. Conditions to consider testing for celiac disease
community (strong recommendation, low quality of evidence;
dissent 0).
CD common CD less common but treatable

Key concepts Symptomatic malabsorption Pulmonary hemosiderosis

Diarrhea with weight loss Male or female infertility
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1. Patients with symptoms, signs, or laboratory evidence suggestive

of malabsorption, such as chronic diarrhea with weight loss, Chronic diarrhea with or without Dyspepsia
steatorrhea, abdominal pain, and bloating, should be tested for abdominal pain
CD. Chronic iron deficiency and Amenorrhea
2. Patients with symptoms, signs, or laboratory evidence for which unexplained anemia
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CD is a treatable cause should be considered for testing for CD.

Metabolic bone disease and premature Chronic fatigue
3. Patients with a first-degree family member who has a confirmed
osteoporosis
diagnosis of CD should be tested whether they show possible
signs or symptoms or laboratory evidence of CD. Postprandial bloating and gaseousness Apparent malabsorption of thyroid
4. Consider testing of asymptomatic relatives with a first-degree replacement medication
family member who has a confirmed diagnosis of CD. Unexplained weight loss Epilepsy or ataxia
Abnormal elevated liver enzymes Constipation
Incidental discovery of villous atrophy Recurrent abdominal pain
Background endoscopically or histologically
The prevalence of CD is rising and detection is improving, but
there is still a large burden of undetected disease. Testing symp- Dermatitis herpetiformis Chronic arthralgia
tomatic individuals with classical presentation (diarrhea and Peripheral neuropathy “Brain fog”
weight loss) is insufficient to detect most persons with CD. Oral aphthous ulcers Recurrent headache or migraine
Strategies to increase detection of CD cases are controversial and
Growth failure
include testing certain groups at increased risk (e.g., first-degree
family members) called case finding and screening of asymp- Discolored teeth or developmentally
tomatic individuals in the general population. Mass screening of synchronous enamel loss
asymptomatic individuals is not supported because CD does not Thyroid disease
fulfill some of the major World Health Organization criteria Irritable bowel syndrome
(Wilson and Junger) for mass screening, specifically the criteria
Down and Turner syndromes
that the natural history of the condition, including development
of latent-to-declared disease, should be adequately understood Unexplained recurrent pancreatitis
and there should be an agreed policy on whom to treat as patients. CD, celiac disease; GFD, gluten-free diet.
Case finding is the current preferred strategy to increase detection Conditions in which CD occurs more frequently than in the general population and for
of cases, although the pros and cons of this approach are still a whom a GFD may be beneficial are listed on the left column. On the right column are
matter of debate. conditions in which CD is a less common, but reversible, treatable cause.

Evidence and rationale

Patients with symptoms, signs, or laboratory evidence suggestive present in many ways. Currently, active case finding (serologic
of malabsorption, such as chronic diarrhea with weight loss, testing for CD in patients with symptoms or conditions closely
steatorrhea, irritable bowel syndrome, abdominal pain, and associated with CD) is the favored strategy to increase detection of
bloating, should be considered for testing for CD. CD is one of the CD (1,123). Active case finding may increase detection of CD
most common causes of chronic malabsorption (119). This re- among patients with symptoms attending a primary care office,
sults from injury to the small intestine with loss of absorptive although this strategy is insufficient to detect most patients with
surface area, reduction of digestive enzymes, and consequential CD (121). There is no consensus about which symptoms, labo-
impaired absorption of micronutrients such as fat-soluble vita- ratory abnormalities, and/or associated diseases require evalua-
mins, iron, and potentially B12 and folic acid (3). In addition, the tion for CD. The frequency of CD in common clinical scenarios
inflammation exacerbates symptoms of malabsorption by caus- varies from modestly elevated, such as irritable bowel syndrome,
ing net secretion of fluid that can result in diarrhea. The failure of to substantially elevated, such as unexplained iron deficiency
absorption of adequate calories leads to weight loss, and the anemia (124–126) (Table 4).
maldigestion results in abdominal pain and bloating. These are The complexity of deciding who to test could be appreciated
common symptoms associated with CD (120). using the example of dyspepsia. Prevalence of biopsy-proven CD in
In contrast to mass screening, case finding among high- patients with dyspepsia is 1%, which is similar to the general pop-
prevalence groups may prove to be effective in clinical practice ulation (127). Systematic screening for CD is not recommended
and perhaps lead to a positive cost-benefit ratio (121). However, because the prevalence of the disease is not higher than that in the
recent evidence suggests that case finding is insufficient to detect general population. However, treatment of dyspepsia could be a
most persons with undiagnosed CD at the population level (122). clinical challenge. Endoscopy may be appropriate for patients who
Patients with symptoms or syndromes for which CD is a treatable continue to have dyspepsia despite initial therapy, those who were 55
cause should be considered for testing for CD because this con- years and older, and/or those with alarm symptoms (128). Dyspepsia
dition remains underdiagnosed in the United States (2) and may as a symptom of CD will readily respond to the GFD (129). Thus,

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 72 Rubio-Tapia et al.

evaluation for CD could be considered in patients with unexplained management of type I diabetes is mixed. Some data suggest an
dyspepsia after initial investigation. In addition, obtaining duodenal increase in absorption, leading to an increased insulin dose. Other
biopsies in patients with dyspepsia who are undergoing upper en- data suggest improvement of diabetes controlled by reduction of
doscopy should be considered. hypoglycemic events, especially postprandially.
Patients with a first-degree family member who has a confirmed
diagnosis of CD should be tested for CD. The frequency of CD is Future research
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substantially increased in patients who have a first-degree family

member affected with CD (130). The precise risk is highest in • What is the effect of screening for CD among asymptomatic
monozygous twins, next HLA-matched siblings, siblings, and then average-risk and high-risk populations on quality of life and
morbidity?
finally, parents and children of patients with CD (18). A lower rate
probably applies to second-degree relatives. Members of families • What is the rate of seroconversion across the life course for
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individuals at increased risk of developing CD, and what is the

who have more than 1 individual already identified with CD are at
optimal serologic screening interval?
higher risk of CD, and recommendations for screening should ex-
tend to all other family members including second-degree relatives
(131). The estimates of prevalence of CD in family members vary Testing in Children
substantially with 1 large multicenter study in the United States, 8. Are TTGA and DGP antibodies in combination more accurate in
showing a rate as low as 5% in both first-degree relatives and diagnosing CD in children younger than 2 years compared with
second-degree relatives (18). Other studies, especially those that are TTG alone?
community-based, show a rate that is substantially higher affecting
up to 20% in siblings and 10% in other first-degree relatives (130). Recommendation
The clinical implications are that newly diagnosed patients with CD 8A. We recommend the immunoglobulin IgA anti-TTG antibody
should inform their first-degree family members of the potential (TTG-IgA) as the preferred single test for the detection of CD in
increased risk for CD and the recommendation for testing. In ad- children younger than 2 years who are not IgA-deficient (strong
dition, healthcare providers should determine whether there is a recommendation, moderate quality of evidence; dissent 0).
family history of CD and, if so, consider screening the patient. 8B. We recommend that testing for CD in children with IgA
Patients who are identified with CD through a screening process deficiency be performed using IgG-based antibodies (DGP-IgG
often have symptoms that may not have been previously explained. or TTG-IgG) (strong recommendation; moderate quality of
Others may have symptoms that were not considered abnormal evidence; dissent 0).
until after they initiated a GFD (132). Screen-detected asymptom-
atic patients remain without symptoms after the onset of a GFD. Key concepts
Most patients with CD identified on the basis of screening reported
1. TTG-IgA and EMA-IgA are reported to be less accurate in children
dietary adherence and improvements in quality of life on the GFD younger than 2 years.
(133). A small proportion of patients, however, report increased
2. Current guidelines recommend that testing for CD in children
health-related anxiety after diagnosis (134). Satisfaction with the younger than 2 years include both TTG-IgA and DGP-IgG.
diagnosis was high (93%).
In patients with elevated serum liver enzymes, CD should be
considered among the explanations for this condition (135). Abnor-
mal liver blood tests, particularly elevations of alanine aminotrans- Background
ferase and aspartate aminotransferase, are commonly seen in clinical Serology testing plays a central role for screening children at risk
care, although the prevalence of clinically significant liver disease is low of CD including children younger than than 2 years. Controversy
(136). Hypertransaminasemia in CD is often a subclinical finding that exists about the best serology approach for children younger than
is gluten-dependent. Patients with unexplained elevation of liver en- 2 years.
zymes should be assessed for CD. There are reasonable data to
show that gluten-dependent hypertransaminasemia will normalize in Evidence and rationale
most patients on a GFD. Rarely, CD can be associated with severe liver Previous guidelines on the diagnosis and treatment of CD rec-
disease (137). ommend that a combination of TTG and DGP tests be used to
Patients with type I diabetes mellitus should be tested for CD if test for CD in children younger than 2 years (1,139). This rec-
there are any suggestive symptoms or signs. There is evidence that ommendation was based on the belief that the TTG and EMA
CD is substantially more common in patients with type I diabetes tests are less accurate in very young children. In support of this
than in the general White population. The estimates vary between belief, a study published in 1991 (140) identified 32 of 277
3% and 10% (138). In children, it has been suggested that yearly or children younger than 2 years with histological feature sugges-
every-other-year screening for CD be undertaken using serology. tive of CD who were negative for EMA but positive for anti-
Patients with type I diabetes who are undergoing upper endos- gliadin antibodies (AGA). However, CD was never confirmed
copy should undergo duodenal biopsies to rule out CD if previous beyond doubt with subsequent challenges and repeat biopsies in
CD testing has not been undertaken. all these cases. A more recent study involving 251 IgA-sufficient
Some evidence suggests that there is added disease burden to children with CD younger than 18 months found antigliadin-
patients already struggling with the management of type I di- IgA (AGA-IgA) antibodies to be more sensitive than either
abetes. In addition, there is good evidence that gastrointestinal TTG-IgA or EMA-IgA (141). Overall in this age group, the
symptoms present at diagnosis will respond to a GFD with overall AGA-IgA was elevated in 97% of cases while TTG-IgA and
improvement in quality of life related to GI symptoms. The im- EMA-IgA were elevated in 83%. All children aged between 18
pact of the identification and treatment of CD on the and 23.9 months had elevated AGA-IgA, and all but one had

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 Celiac Disease Guidelines 73

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