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Celiac Disease in Children: A 2023 Update

Article in The Indian Journal of Pediatrics · June 2023

DOI: 10.1007/s12098-023-04659-w

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Indian Journal of Pediatrics (May 2024) 91(5):481–489
https://doi.org/10.1007/s12098-023-04659-w

REVIEW ARTICLE

Celiac Disease in Children: A 2023 Update

Rishi Bolia1 · Nikhil Thapar1,2,3

Received: 1 February 2023 / Accepted: 19 April 2023 / Published online: 8 June 2023
© Crown 2023

Abstract
Celiac disease (CeD) is a chronic immune-mediated enteropathy, which occurs in genetically predisposed individuals by
the ingestion of gluten proteins present in wheat, barley and rye. The global pooled prevalence of CeD is 0.7% and it has
been reported from nations all around the globe and can affect individuals of any age. It has a wide clinical spectrum rang-
ing from being asymptomatic to being symptomatic with severe manifestations. Though initial descriptions of CeD focused
on the classical presentation with gastrointestinal manifestations, in recent years it has been found that more patients have
non-classical manifestations such as anemia, osteoporosis, increased transaminases, failure to thrive or short stature. The
definitive diagnosis of CeD is based on a combination of clinical history, serologic testing with/without examination of
duodenal biopsies. The preferred initial serologic test regardless of age for the detection of CeD is the tissue transglutami-
nase (IgA anti-tTG). Children with a high tTG-IgA (≥10 ULN) AND a positive anti-endomysial IgA antibody (EMA) can
be diagnosed to have CeD without the need for duodenal biopsies. The rest should undergo biopsies with at least 4 biopsies
from the distal duodenum and at least 1 from the bulb. A correctly orientated biopsy showing increased intraepithelial cells
and a villous to crypt ratio of <2 is suggestive of CeD. The management of CeD is a lifelong complete dietary avoidance
of gluten. IgA-TGA acts as a surrogate marker for healing of the small-bowel mucosa and should be performed every 6 mo
until normalization and then every 12–24 mo thereafter.

Keywords Celiac disease · Tissue transglutaminase · Anti-endomysial antibody · Gluten · Diarrhea

Introduction Epidemiology

Celiac disease (CeD) is a chronic immune-mediated enter- CeD has been reported from nations all around the globe
opathy, which occurs in genetically predisposed individuals and can affect individuals of any age. The global pooled
by the ingestion of gluten proteins present in wheat, barley prevalence of CeD based on serology is 1.4% and based on
and rye. It has a wide clinical spectrum ranging from being biopsy results is 0.7% with a higher prevalence in females
asymptomatic to being symptomatic with severe manifesta- as compared to male individuals [1, 2]. The highest preva-
tions. As a result of its varied presentation, it runs the risk lence has been reported from Europe and Oceania (0.8%)
of remaining undiagnosed or the diagnosis being delayed in followed by Asia (0.6%), North America and Africa (0.5%)
a significant number of individuals. and South America (0.4%) [1]. In India, CeD affects ~1%
of the North Indian population and about half of that in
other parts of the country. It is infrequent or absent in
Southern India [3].
* Rishi Bolia Global epidemiology studies have documented an overall
[email protected] rapidly rising incidence and prevalence with stabilization
1
Department of Gastroenterology, Hepatology and Liver
in some regions (notably Sweden and Finland) [2]. This
Transplant, Queensland Children’s Hospital, 501, Stanley increase can not only be attributed to increased detection
Street, South Brisbane, QLD 4101, Australia because of improvements in diagnostic tests and increased
2
School of Medicine, University of Queensland, Brisbane, awareness but also a true increase because of changes
Australia in dietary practices and environmental factors. Interest-
3
Woolworths Centre for Child Nutrition Research, Queensland ingly, on the other hand, despite increased recognition and
University of Technology, Brisbane, Australia

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482 Indian Journal of Pediatrics (May 2024) 91(5):481–489

simplified diagnostic criteria CeD still remains underdi- Environmental Factors

agnosed in certain deprived socio-economic groups and
developing countries [4, 5]. There are emerging data to suggest that the risk of developing
The prevalence of CeD is significantly greater in children celiac disease correlates with the amount of gluten intake in
than adults. In a pooled analysis, children were 2 times more the early part of life. In a large cohort study it was observed
likely to be diagnosed with CeD compared to adults [1]. There that a higher consumption of gluten in genetically at-risk
has been a sharp increase in the age at diagnosis of pediatric individuals during the first few years of life was associated
CeD in the last 2 decades. In a recently published systematic with a higher risk of developing CeD [12]. In this study it was
review of the incidence of pediatric CeD in Europe it was found that the risk of developing CeD significantly increased
found that the median age of diagnosis has increased from 1.9 if the child consumed more than 2 g/d of gluten at around 2 y
y in the 1990s to 7.6 y since the year 2000 [6]. of age, which corresponds to approximately one slice (35 g)
of bread or 150 g of cooked pasta. This risk increased lin-
early with further higher gluten intake. However, these results
Etiology and Risk Factors were obtained on a post-hoc analysis and need confirmation.
The source of gluten may also have a bearing on the risk
Genetics
of developing CeD. In a prospective study that assessed the
sources of gluten intake during the first couple of years of
CeD occurs in genetically predisposed individuals who
life it was found that porridge, bread and milk cereal drink
express certain specific human leukocyte antigens [HLA-
(a formula composed of milk powder and flour) appear to
DQ2 ((DQ2.5; DQA1*05/DQB1*02), and HLA-DQ8
increase the risk of CeD in genetically-predisposed children
(DQA1*03/DQB1*0302)] related to the DQ region. Most
compared to pasta, breakfast cereals, pancakes, sweet baked
patients (~90–95%) carry a variant of HLA-DQ2, whereas
goods, or crackers [13]. However, more data is warranted to
the remaining carry HLA-DQ8.
confirm these finding before any definite recommendations
It is postulated that the “gene dose” has an effect on the
regarding dietary strategies for children genetically suscep-
clinical phenotype with those possessing a double dose of
tible to CeD can be made.
HLA-DQB1*02 more likely to have villous atrophy and
It was initially speculated that the timing of gluten introduc-
classical manifestations of CeD [7].
tion may be a risk factor for CeD. However, a large randomized-
HLA-DQ2 or HLA-DQ8 are expressed in 30%–35% of
controlled trial (RCT) and subsequently a meta-analysis showed
the populations where CeD is prevalent, with only ∼2%–5%
that the rates of CeD in high-risk children were similar whether
of these carriers developing the disease [8]. Thus a large pro-
gluten was introduced at 4, 6 or 12 mo of age [14, 15].
portion of patients who carry these genes will never develop
There is some data to suggest that infections and antibiotic
CeD. This also implicates other genetic as well as environ-
exposure in early childhood may potentiate the subsequent
mental factors as contributors to the manifestations of CeD.
development of CeD [16, 17]. In a systematic review it was
CeD has been found to have a 7.5% pooled prevalence
found that the occurrence of any infection in early childhood
among first degree relatives [9]. In a recent study it has been
increases the odds of developing CeD by 37%. It is speculated
reported that the prevalence may be even higher (~17%) than
that these infections and/or antibiotics lead to changes in the
previous reports. These children from families with CeD, are
gut microbiome affecting the intestinal immune responses
more likely to develop CeD at a young age [10]. The risk var-
and mucosal barrier function and creating a proinflammatory
ies in the first-degree relatives according to their relationship
milieu for gluten to trigger CeD.
with the index patient with the highest prevalence reported in
Breastfeeding and the modality of delivery in infants at
siblings [9]. Intriguingly females have been reported to be at a
risk for CeD have been postulated to affect the incidence of
higher risk compared to their male counterparts. The presence
the disease. However, data supporting the role of these fac-
of HLA-DQ2 homozygosity has also been reported to be an
tors as a risk for the development of CeD is limited and the
important risk-factor in this cohort. A prediction application
associations identified in these studies are not causal [18, 19].
(https://​hputt​er.​shiny​apps.​io/​preve​ntcd/) has been developed
The pathophysiology of CeD has been described in Fig. 1.
to calculate the individual risk of developing CeD in these
“at-risk” children based on the above-described factors [10].
Apart from those with first-degree relatives of patients
Clinical Presentation
with CeD, patients with autoimmune conditions (such as
type-1 diabetes mellitus and thyroid diseases) or genetic
The clinical spectrum ranges from essentially asymptomatic
disorders such as IgA deficiency, Down syndrome, Turner
to symptomatic individuals. The initial descriptions of CeD
syndrome, and Williams-Beuren syndrome are also at
focused on the classical presentation with gastrointestinal
high-risk for the development of CeD [11].

13
Indian Journal of Pediatrics (May 2024) 91(5):481–489 483

Gluten
Paral Degradaon
Pepdase
(Laglutenase) Intesnal
Lumen

Intesnal
Epithelium
Tight Juncon Regulaon
(Larazode)
TJ
An-IL15 IL15

Lymphocyte IL21,IFN-Y
Lymphocyte Trafficking

TG2 Inhibitors
Pro-inflammatory TG2
cascade
Lamina
HLA DQ2/8 Propria

Immune tolerant Therapy

APC (Nexvax2)

TLR
APC
CD4

Deamidaon

Plasma
CD4

Cell
B-

Cell

Fig. 1  Pathophysiology of Celiac disease and therapeutic targets in development. APC Antigen presenting cell, TG2 Transglutaminase2, TJ
Tight junction, TLR Toll-like receptor. Text in red denote therapeutic targets in development

manifestations including diarrhea, malabsorption and nutri- definitions for terms relating to CeD. This group identified
ent deficiencies secondary to small bowel mucosal disease. the following types of clinical presentations of CeD: clas-
However, over the years it has been found that many patients sic, non-classic, subclinical, potential and refractory [20].
present with non-classical manifestations such as anemia These terms have been summarised in Table 1.
unresponsive to oral iron therapy, osteoporosis, increase in Recent trends suggest that there has been a rise in
transaminases, infertility, short stature or failure to thrive. patients with non-classical symptoms. In a case-finding
A large number of vague and confusing terms such as Italian study the disease was sub-clinical in 64%, classical
silent, asymptomatic, latent, subclinical, atypical etc. were in 28%, non-classical in 7%, and potential in 1% [21]. This
used to describe the spectrum of disorders related to CeD. suggests that a large proportion of patients are sub-clinical
In 2013, a multidisciplinary Task-force of physicians pro- with only a small proportion visible clinically leading to
posed the “Oslo classification” of CeD providing uniform the use of the term the “Celiac Iceberg”.

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484 Indian Journal of Pediatrics (May 2024) 91(5):481–489

Table 1  Clinical features of Celiac disease

Clinical Presentation Details

Classical With signs and symptoms of malabsorption

Diarrhea, loss of appetite, abdominal distention, failure to thrive, bloating, abdominal pain and muscle wasting
Non-classic Without signs and symptoms of malabsorption
These include –
Chronic constipation not responding to usual treatment
Chronic abdominal pain
Dermatitis herpetiformis
Recurrent aphthous stomatitis
Permanent enamel hypoplasia
Iron-deficient anemia resistant to oral iron supplements
Short stature, delayed puberty
Abnormal liver biochemistry
Arthritis
Osteopenia/osteoporosis
Irritability, chronic fatigue, neuropathy
Unexplained infertility
Subclinical Disease that is below the threshold of clinical detection without signs or symptoms sufficient to trigger Celiac disease
(CeD) testing in routine practice
Potential Normal small intestinal mucosa who are at increased risk of developing CeD as indicated by positive CeD serology
Potential CeD requires clinical and laboratory surveillance (serology, further biopsies) to monitor possible evolution to
villous atrophy
Refractory Persistent or recurrent malabsorptive symptoms and signs with villous atrophy despite a strict gluten-free diet for more
than 12 mo

Diagnosis In children <2 y of age the addition of IgG anti-DGP may

increase the diagnostic sensitivity and may be considered if
The definitive diagnosis of Celiac disease is based on a com- there is a high index of clinical suspicion and IgA ant-tTG is
bination of clinical history, serologic testing with/without negative [24]. This is because DGP-IgG precedes tTG-IgA
examination of duodenal biopsies. seroconversion in children in 80% of cases [25]. It is, how-
ever, less specific than tTG, and so, even in this young age
Diagnostic Tools group, tTG is the preferred initial screening test with DGP
reserved for those with a high clinical suspicion.
Serology A positive IgA anti-tTG should prompt further evalua-
tion (see diagnostic algorithm – Fig. 2) to confirm CeD [23].
Serological tests are the first screening tests performed when A positive anti-tTG serology alone does not confirm the
evaluating a patient for CeD. The three commonest specific diagnosis of CeD as false positive serologic tests may occur
serological tests available for diagnosing CeD are - IgA in a number of conditions including chronic liver disease,
antibody to tissue transglutaminase (IgA anti-tTG), anti- rheumatoid arthritis, inflammatory bowel disease and other
endomysial IgA antibody (EMA) and anti-deamidated glia- autoimmune diseases. However, high values of tTG-IgA cor-
din peptide (DGP) IgA and IgG. relate with a greater degree of villous atrophy and a cut-off
The preferred initial serologic test regardless of age for the of ≥10 ULN has a >97% positive predictive value (PPV) for
detection of CeD is the IgA anti-tTG, which shows a sensitiv- CeD diagnosis [23]. Children with high (≥10 ULN) serum
ity and specificity of around 97.7% and 70.2% respectively levels of tTG-IgA should be evaluated for CeD diagnosis
[22]. This test is available as an enzyme linked immunosorb- using a “non-biopsy” approach (Fig. 2).
ent assay. As the test is IgA based, children who are IgA EMA is detected by immunofluorescence using monkey
deficient may have a false-negative tTG and so testing for esophagus or human umbilical cord sections and is opera-
total IgA levels should be done simultaneously [23]. Apart tor dependent. The test has a higher specificity (93.8%) and is
from IgA deficiency other factors that may contribute to a used as a confirmatory test in a second blood sample in cases
false-negative tTG serology are – age <2 y, laboratory error, where the tTG-IgA is ≥10 ULN (see diagnostic algorithm)
reduced gluten in the diet and the use of corticosteroids or [22, 23]. Children who meet this criteria i.e., a tTG-IgA
immunomodulators. It is important that these points should of ≥10 ULN AND a positive EMA have a 99.75% PPV for
be kept in mind while interpreting a tTG serology report. CeD diagnosis and can be diagnosed without the need for

13
Indian Journal of Pediatrics (May 2024) 91(5):481–489 485

- Classical or Non-classical symptoms of CeD

- High-risk group for CeD

IgA-an tTG
Total IgA levels

IgA-an tTG negave IgA-an tTG negave

IgA-an tTG posive
Normal IgA levels Low IgA levels

Consider tTG
concentraon Consider risk of false IgG-an tTG, DGP or
negave serology EMA
( X ULN )
- Inadequate gluten intake
- Age <2 y
Negave
- Immunosuppresive
medicaons NOT
tTG >=10 ULN tTG <10 ULN
Celiac Disease
No Risk Posive
If age <2 y – IgG an-
Test for EMA on a Duodenal Biopsy NOT Celiac Disease DGP
Duodenal Biopsy
separate blood sample Duodenal Biopsy
Negave

Posive
Histopathology Histopathology
*Celiac Disease Marsh 2-3 Marsh 0-1

NOT
Celiac Disease
Celiac Disease

Fig. 2  Diagnostic Algorithm for Celiac Disease. CeD Celiac disease, type 1 diabetes mellitus. The Indian Council of Medical Research
DGP Deaminated gliadin peptide, EMA Endomysial IgA antibody, does not recommend a non-biopsy approach as this approach has not
tTG - IgA IgA antibody to tissue transglutaminase, ULN Upper limit been validated in India
of normal.*Non-biopsy approach is not validated in children with

duodenal biopsies [26]. The addition of EMA to the algo- reduced folds of duodenum. At least 4 biopsies from the dis-
rithm decreases the probability of a false positive diagnosis tal duodenum and at least 1 from the duodenal bulb should
of CeD [23]. be taken for histology assessment during a gluten-containing
In a patient with selective IgA deficiency an IgG based diet [27]. In a meta-analysis of 11 pediatric studies it was
test such as IgG anti-tTG Ab or IgG anti-DGP Ab should be found that the addition of a duodenal bulb biopsy increased
performed. The no-biopsy approach is not validated in this the diagnostic yield by 8% [28]. The reading of biopsies
cohort with IgA deficiency. should be performed on properly orientated biopsies using
the modified Marsh-Oberhuber classification of villous
Histopathology abnormalities, which grades severity of villous atrophy based
on two parameters i.e., increase in intraepithelial lympho-
All children who do not meet the serological diagnostic cri- cytes (IELs) and reduced villous height to crypt depth ratio.
teria for CeD should undergo a duodenal biopsy. The vari- A correctly orientated biopsy showing >25 IELs/100 epithe-
ous endoscopic duodenal appearances which suggest CeD lial cells and a villous to crypt ratio of <2 (Marsh Grade 2–3)
include mosaic pattern, scalloped folds of duodenum, and indicates significant mucosal lesions [23].

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486 Indian Journal of Pediatrics (May 2024) 91(5):481–489

The Indian Council of Medical Research (ICMR) recom- wheat, barley and rye. Oats does not contain gluten but
mends that changes in small intestinal biopsy are essential for often gets contaminated during milling. About 5% of CeD
the diagnosis of CeD as the “no-biopsy” approach has not been patients may also be intolerant to pure oats. Proper dietary
validated in India. This expert group also recommends keeping counselling, ideally by an accredited pediatric dietician, at
the IEL threshold at >40 IELs/100 epithelial cells as IELs may the time of diagnosis and periodic regular reinforcement
be increased in conditions like giardiasis and tropical sprue [29]. for the need of strict dietary adherence is required. Patients
The “no-biopsy” criteria is also not validated for children and families need to be educated about sources of acciden-
with type 1 diabetes mellitus (T1DM) and duodenal biopsies tal contamination of gluten. Continued exposure to even
should be performed in all as a part of the diagnostic work-up. small amounts of gluten leads to persistence of the disease.
All patients and their families should be provided oral and
Genetic Studies written information about the disease, benefits of being com-
pliant to GFD and with a list of food items which are safe
While the majority of patients with CeD are HLA-DQ2/- and which are not safe for them. They should be encouraged
DQ8 homozygous, heterozygous or compound heterozy- to check labels of packaged foods, and only those labelled
gous, HLA typing is not required routinely for the diagnosis as “gluten-free” should be consumed. A product is consid-
of CeD. The sensitivity of HLA-DQ2 and HLA-DQ8 typing ered gluten-free if the gluten content is <20 parts per mil-
for detection of CeD is 98% and specificity 45% [30]. The lion. Emotional and practical support with other individuals
negative likelihood ratio for CeD is low making it a more with CeD (celiac support groups etc.) should be provided to
useful test for “ruling out” CeD rather than diagnosing it. reduce feelings of social isolation.
CeD patients should be followed at regular intervals. The
Diagnostic Algorithm first visit should be scheduled 3–6 mo after the diagnosis.
During this visit the child should be monitored for compli-
The following diagnostic algorithm has been suggested for ance to gluten-free diet, their anthropometric parameters and
the diagnosis of celiac disease (Fig. 2). Patients with dis- the resolution of symptoms. A complete blood count, iron
cordance between serology, histology, and HLA DQ2/DQ8 studies, Vitamin D levels and liver function tests should be
positivity should be evaluated on a patient-by-patient basis. performed. Any abnormality should be followed and defi-
This often includes re-cutting biopsies and/or a second opin- ciencies corrected until normalization. IgA-TGA using the
ion from the pathologist. There is some data to suggest that same assay as at diagnosis acts as a surrogate marker for
evaluating the presence of intestinal anti-TG2 extracellular healing of the small-bowel mucosa and should be performed
IgA deposits by using double immunofluorescence may be every 6 mo until normalization and then every 12–24 mo
a useful complementary tool to identify those with CeD. thereafter [33]. Screening for thyroid disease should be done
These deposits appear early in the course of the disease and and hepatitis B virus (HBV) antibody levels should be meas-
may help in identifying CeD before the development of other ured in previously immunized patients. This is because it
histological abnormalities [31]. has been found that children with CeD have a lower immune
At times one encounters a patient with self-initiated glu- response following HBV vaccination [34]. Children with
ten-free diet (GFD) or those who have been started on GFD inadequate anti-Hbs levels should receive a booster.
without confirmatory diagnostic testing. A gluten challenge
should be considered in such a scenario given the signifi-
cance of the long-term clinical implications. Gluten chal- Pharmacologic Management
lenge usually constitutes consuming a diet containing at least
10 g of gluten per day for 6–8 wk and seems to be the most At the time of initial diagnosis, patients with CeD should
accepted way to induce histologic changes. This long 6–8 wk be given vitamin D and iron supplements to overcome
period of gluten challenge is burdensome and recent research deficiencies and replenish nutrient stores.
into less invasive, lower-dose, shorter-duration challenges are Therapies that would permit the (or cover accidental) inges-
showing promising results [32]. It is likely that an abbrevi- tion of gluten in patients of CeD are currently being investigated.
ated gluten challenge may be the norm in the future. These include medications that bring about gluten detoxification
(glutenases), inhibit intestinal permeability (larazotide), Inhibit
Management transglutaminase 2 or modulate the immune response (Nex-
vax2). None of these therapies are currently recommended for
Diet routine patient care. These therapies appear promising (Fig. 1)
and there is hope that in the next 5 y pharmacological agents that
Lifelong complete dietary avoidance of gluten is the cor- can be used adjunctively with a GFD for accidental or intentional
nerstone of the management of CeD. Gluten is found in gluten exposures would have been approved [35–38].

13
Indian Journal of Pediatrics (May 2024) 91(5):481–489 487

Fig. 3  Algorithm for investigat-

ing children with Celiac disease Celiac disease on gluten-free diet
with persisting symptoms. tTG with persis ng symptoms
- IgA IgA antibody to tissue
transglutaminase. *Some indi-
Review original
viduals are sensitive to small
diagnosis
traces of gluten (<20/ppm)

Confirmed
diagnosis of
Celiac disease

tTG-IgA

Elevated Normal

Compliant
Diete cs Review Gastroscopy
and biopsies
Non-adherence
Gluten super-
sensi ve*
Persis ng Normal villous
villous atrophy architecture

Consider
Refractory Colonoscopy and biopsies
Celiac disease
Fecal Elastase
Fecal Calprotec n
Stool microscopy and culture
Evaluate for small intes nal bacterial overgrowth,
Lactose intolerance and Fructose intolerance
Blood inves ga ons (including inflammatory markers and
thyroid profile)

Microscopic coli s
Exocrine pancrea c
insufficiency
Giardiasis
Hyperthyroidism

Func onal gastrointes nal

All Inves ga ons normal disorders

Prognosis and Complications diet. An improvement in the overall general well-being is

generally one of the first signs of response. The symptoms,
The prognosis of celiac disease is good with the large major- signs and laboratory abnormalities should resolve within
ity of children having a complete and long-lasting resolution 6–12 mo of initiation of a gluten-free diet. Serologic titers
of symptoms on a gluten-free diet alone. Patients start show- fall soon after initiating a GFD. In those with persisting
ing a response within weeks of the initiation of a gluten-free symptoms and/or lack of decreasing tTG levels 6–12 mo

13
488 Indian Journal of Pediatrics (May 2024) 91(5):481–489

after GFD initiation the most common cause is ongoing 3. Ramakrishna BS, Makharia GK, Chetri K, et al. Prevalence of
advertent/inadvertent gluten exposure. Causes of ongoing adult celiac disease in India: Regional variations and associations.
Am J Gastroenterol. 2016;111:115–23.
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irritable bowel syndrome, lactose intolerance, microscopic disease is being missed in over 80% of children particularly in
colitis, pancreatic insufficiency and bacterial overgrowth those from socioeconomically deprived backgrounds. Eur J Pedi-
[39]. An algorithmic approach to children who continue to atr. 2021;180:1941–6.
5. Poddighe D, Abdukhakimova D. Celiac disease in Asia beyond
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A small subset of CeD patients are refractory to a gluten- and diagnostic barriers. World J Gastroenterol. 2021;27:2251–6.
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disease across Europe. Aliment Pharmacol Ther. 2021;54:109–28.
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measurement of gluten immunogenic peptides (GIP) in the 11. Raiteri A, Granito A, Giamperoli A, Catenaro T, Negrini G,
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lymphoma and non-Hodgkin’s lymphoma. While the mortal- children: The Environmental Determinants of Diabetes in the
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Authors' Contributions RB: Concept and design, drafting of the article, HLA status, and the risk of celiac disease in children. N Engl J
final approval of the version to be published; NT: Critical revision, final Med. 2014;371:1295–303.
approval of the version to be published. NT will act as the guarantor 16. Kemppainen KM, Lynch KF, Liu E, et al. Factors that increase risk
of this manucript. of celiac disease autoimmunity after a gastrointestinal infection in
early life. Clin Gastroenterol Hepatol. 2017;15:694–702.e5.
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