ORIGINAL ARTICLE: GASTROENTEROLOGY: CELIAC DISEASE

Extraintestinal Manifestations of Celiac Disease:

Effectiveness of the Gluten-Free Diet

Hilary Jericho, yNaire Sansotta, and Stefano Guandalini

ABSTRACT

Objective: The aim of the study was to evaluate the effectiveness of the
What Is Known
gluten-free diet (GFD) on extraintestinal symptoms in pediatric and adult
celiac populations at the University of Chicago.  Celiac disease is a complex autoimmune disease,
Methods: We conducted a retrospective chart review of the University of
triggered by the ingestion of gluten in genetically
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Chicago Celiac Center clinic charts from January 2002 to October 2014.
Demographics, serologic testing, intestinal biopsies, and extraintestinal
symptoms at presentation, 12, 24, and >24 months were recorded.
Extraintestinal symptoms included abnormal liver enzymes, arthralgia/
arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia,
stomatitis, myalgias, psychiatric disorders, rashes, seizures, neuropathy,
short stature, delayed puberty, osteoporosis, and infertility.
Results: A total of 737 patients with biopsy-confirmed celiac disease or
skin biopsy–confirmed dermatitis herpetiformis were included. Patients lost
to follow-up, or with insufficient data were excluded leaving 328 patients
(157 pediatrics younger than 18 years). For pediatrics, the female to male ratio
was 2:1 and the mean age at diagnosis was 8.9 years. For adults, 4:1 and
40.6 years old. Extraintestinal symptom rates were similar in children (60%)
and adults (62%). Short stature (33%), fatigue (28%), and headache (20%)
were most common in children. Iron deficiency anemia (48%), fatigue (37%),
and headache/psychiatric disorders (24%) were common in adults. Children
had faster/higher rates of symptom resolution compared with adults. Twenty-
eight percent of children with unresolved short stature on a GFD were found to
have other comorbidities.
Conclusions: Children and adults with celiac disease have similar rates of
extraintestinal manifestations. In children short stature, fatigue, and headache
were most common, whereas anemia, fatigue, and headache/psychiatric
disorders were most common in adults. Children on a strict GFD showed
faster and higher rates of symptom resolution as compared to adults.
Unresponsive children with short stature must be assessed for comorbidities.
Key Words: adult, gastrointestinal, pediatric
(JPGN 2017;65: 75–79)
Received November 23, 2015; accepted September 19, 2016.
From the Department of Pediatrics, University of Chicago Medicine
Comer Children’s Hospital, Chicago, IL, and the yDepartment of
Pediatrics, Università degli Studi di Verona, Verona, Italy.
Address correspondence and reprint requests to Hilary Jericho, MD,
Division of Gastroenterology, Hepatology, Nutrition, The University of
Chicago Medicine Comer Children’s Hospital, 5721 S. Maryland Ave,
Chicago, IL 60637 (e-mail: Hjericho@peds.bsd.uchicago.edu).
Supplemental digital content is available for this article. Direct URL
citations appear in the printed text, and links to the digital files are
provided in the HTML text of this article on the journal’s Web site
(www.jpgn.org).
There are no prior publications or submissions with significant overlapping
information.
This work is not and will not be submitted to any other journal while
under consideration by the Journal of Pediatric Gastroenterology and
Nutrition.
The authors report no conflicts of interest.
Copyright # 2016 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000001420
predisposed individuals.
 Patients present asymptomatically or with gastroin-
testinal and/or extraintestinal symptoms.
 The gluten-free diet is the only current treatment for
resolving gastrointestinal manifestations, but scarce
information is available on its effectiveness in resol-
ving extraintestinal manifestations in children and
in adults.
What Is New
 Children and adults have similar rates of extraintest-
inal manifestations of celiac disease.
 Children on a strict gluten-free diet show faster and
higher rates of symptom resolution compared
with adults.
 Unresponsive children with short stature must be
assessed for comorbidities.
C eliac disease (CD) is a complex autoimmune disease, trig-
gered by the ingestion of gluten (the major storage protein in
wheat, barley, and rye) in genetically predisposed individuals,
causing elevated titers of celiac-specific autoantibodies and result-
ing in variable degrees of small intestinal inflammation and a wide
range of gastrointestinal and extraintestinal manifestations (1).
Extraintestinal manifestations of CD can include chronic
fatigue, anemia, osteoporosis, aphthous stomatitis, elevated liver
enzymes, joint/muscle pain, infertility, epilepsy, and peripheral
neuropathy (2)
Currently the only effective treatment of CD is strict, lifelong
adherence to the gluten-free diet (GFD). This usually results in
resolution of small intestinal inflammation (3).
The aim of the present study was to characterize the preva-
lence of extraintestinal manifestations in children and adults with
CD and describe symptom recovery after treatment with a
strict GFD.
PATIENTS AND METHODS
Patients and Data Collection
We conducted a retrospective review of patient records
contained in a registry (prospectively populated) of children
(18 years or younger) and adults (older than 18 years) with CD
followed at the University of Chicago between 2002 and 2014.
Before inclusion in the study, a diagnosis of CD was confirmed

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Jericho et al
according to the present guidelines (1). The criteria for inclusion in
our study were positive serology and Marsh 1–3 findings on biopsy;
tissue transglutaminase immunoglobulin A >10 times normal with
positive endomysial antibody with or without a biopsy; or positive
serology and skin biopsy for dermatitis herpetiformis (DH). In the
case of immunoglobulin A deficiency, deamidated gliadin peptide
immunoglobulin G was used. Exclusion criteria included patients
lost to follow-up or no data available. All patients had clinical and
biochemical follow-ups recorded at diagnosis, between 6 and
12 months, 12 and 24 months, and at a time point from 24 months
onward (2.6 years for children and 2.3 years for adults) and all
children were evaluated by pediatric gastroenterologists, whereas
all adults were evaluated by adult gastroenterologists.
Statistical Methods
McNemar’s chi-square test was used to compare paired
categorical variables. Fisher exact test was used to compare 2
categorical variables. Student t test was used to compare groups.
A P value <0.05 was considered significant. Statistical analyses
were performed by using SAS (version 6; SAS institute Inc.,
Cary NC).
RESULTS
General Characteristics of Patients
After a query of our RedCap registry (populated in a pro-
spective manner by research assistants’ review of physician notes
for explicitly defined variables) we identified 737 pediatric and
adult patients (47% children) with the diagnosis of CD. Three
hundred twenty-eight patients (48% children) met our inclusion
criteria and were enrolled into our study (Fig. 1). The mean age
at diagnosis for children was 8.8 years (range 1.3–17.7 years) and
40.6 years for adults (range 18.3–75.7). Abnormal liver enzymes,
arthralgia/arthritis, alopecia, fatigue, headache, anemia, stomatitis,
FIGURE 1. Patient inclusion and exclusion algorithm.
76
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JPGN  Volume 65, Number 1, July 2017
myalgias, psychiatric disorders, rashes, seizures, neuropathy, short
stature, delayed puberty, osteoporosis, and infertility represented
the most frequent extraintestinal manifestations of CD encountered.
Standardized parameters set forth by the University of Chicago
Medical Center were used to define symptoms with identifiable
‘‘abnormal’’ values such as a total iron <40 and a percentage
saturation <14 to define iron deficiency anemia, Alt >35 for
abnormal liver enzymes, a height >2 standard deviations below
the mean for age and sex for short stature and no secondary sexual
maturation or any sign of puberty by the age of 13 years in girls and
14 years in boys for delayed puberty. Psychiatric and neurological
diagnoses were made by trained professionals in the fields of
pediatric and adult psychiatry and neurology, respectively. All
other symptoms listed above were based on subjective reports from
the patients.
Clinical Symptoms and Resolution After
Gluten-Free Diet
Sixty percent of children and 62% of adults displayed
extraintestinal manifestations of CD (n ¼ 328, 157 younger than
18) alone or in combination with gastrointestinal symptoms. Extra-
intestinal manifestations alone were detected in 18% of children and
9% of adults.
Short stature (33%), fatigue (28%), and headache (20%)
were most common in children and iron deficiency anemia
(48%), fatigue (37%), and headache/psychiatric disorders (24%)
were most common in adults. Short stature and delayed puberty
were only encountered in children, whereas alopecia, infertility,
neuropathy, and osteoporosis were only encountered in adults
(Supplemental Digital Content, Figs. 1 and 2, http://links.lww.
com/MPG/A813).
Children had greater improvements on a GFD as compared to
adults for 71% of shared extraintestinal symptoms (P ¼ 0.001),
although statistical significance was reached for fatigue alone
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JPGN  Volume 65, Number 1, July 2017 Extraintestinal Manifestations of Celiac Disease

(P ¼ 0.002) (Fig. 2). The 2 exceptions were abnormal liver enzyme
(100% vs 88%) and iron deficiency anemia (85% vs 84%) in which
adults had greater rates of improvements as compared to children.
One hundred percent of children and adults with dermatitis herpe-
tiformis and seizure improved on a GFD as did all children with
delayed puberty. Patients with DH did not receive dapsone or other
pharmacologic therapies.
Although 100% of adults had normalization of liver enzymes
on a GFD, a single child (12% of total) failed to improve on GFD. A
liver biopsy demonstrated nonalcoholic fatty liver disease as the
contributor to her persistently elevated liver enzymes.
Thirty-five percent of children with short stature failed to
display catch-up growth on a strict GFD. Of these, 50% were
reported to have persistent short stature not otherwise specified,
22% were felt to have a constitutional growth delay, and 28% were
found to have another underlying condition contributing to their
short stature including inflammatory bowel disease, food aversion,
Turner syndrome, and GH deficiency. Three out of 18 patients with
short stature had bone ages obtained including a 7-year-old boy, 9-
year-old girl, and 3-year-old boy. The first 2 patients had delayed
bone ages, whereas the third was noted to be at chronological age.
From the follow-up notes at 6 years, 5 years, and 3 years, respect-
ively, the patients were noted to continue to display short stature
without a return to their expected height.
Other improvement rates for children were 100% for myalgia
and stomatitis, 84% for iron deficiency anemia (without iron
supplementation, but with a single case of a blood transfusion)
and for poor mood, 83% for unspecified rash, 81% for fatigue, 75%
for arthritis, 73% for arthralgia, 71% for headache, and 59% for
psychiatric disorders by 24 or more months (Fig. 3). Improvement
rates for adults were 85% for iron deficiency anemia, 73% for
unspecified rash and for stomatitis, 69% for arthritis, 57% for
headache, 56% for psychiatric disorders, 54% for arthralgia,
51% for fatigue, and 50% for poor mood and for myalgia by 24
or more months (Fig. 4). Of note, 9% of adult patients with iron
deficiency anemia did receive iron supplementation. In 57% of
those patients their iron deficiency anemia resolved, whereas 43%
persisted despite adhering to a GFD.
Twenty-six percent of children and 49% of adults reportedly
on a strict GFD failed to have improvements in 1 or more of their
extraintestinal symptoms, whereas 63% of children and 80% of
adults reportedly not adhering to the GFD failed to have improve-
ments in their extraintestinal symptoms.
There were no statistically significant differences between
the age at diagnosis (P ¼ 0.23) and sex (P ¼ 0.49) between respon-
ders and nonresponders.
DISCUSSION
Although CD primarily affects the gut, the clinical manifes-
tations of the disease are incredibly diverse with many extraintest-
inal systems affected (4).
To our knowledge, the present study is the first comparing
the prevalence and resolution of extraintestinal manifestations of
CD on a GFD in pediatric and adult celiac populations.
Our series confirmed that one of the most common extra-
intestinal manifestations of CD in children is short stature, and in
some patients, short stature may be the only presenting symptom of
the disease (5). The pathogenesis is unclear but likely due in part to
malabsorption, an abnormality in the endocrine growth axis, or
growth hormone resistance (6).
In our study, 52 children with CD presented with short stature
and 65% showed catch-up growth. Twenty-eight percent of those not
responding were found to have comorbidities consisting of inflamma-
tory bowel disease, food aversion, Turner syndrome, and GH
deficiency. This is highly important because it stresses the need for
a further workup for underlying comorbidities should a pediatric patient
with CD on a strict GFD not display appropriate catch-up growth.
Iron deficiency anemia was found to be the most common
extraintestinal symptom in adults with CD presenting in 48% of
patients. Eighty-five percent of adults with iron deficiency anemia
had resolution, quite similarly to children, 84% of whom resolved
their anemia. Secondary to poorly absorbed iron in the affected

100

90
P = 0.002
80

70

60

% 50
All categories
40 P = 0.001

30 Pediatric responders

Adult responders
20

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Extraintestinal symptoms

FIGURE 2. Extraintestinal symptom response rates on a gluten-free diet (GFD): pediatrics versus adults.

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Jericho et al JPGN  Volume 65, Number 1, July 2017

120

100

80
%

60

40

20

0
Baseline symptom 6−12 months 13−24 months >24 Months

Myalgia Delayed puberty Seizure

Alopecia Mouth sores Dermatitis herpetiformis
Abnormal liver enzymes Iron deficiency anemia Poor mood
Rash Fatigue Arthritis
Arthralgia Headache Short stature
Psychiatric disorders

FIGURE 3. Pediatric extraintestinal symptoms: rates of improvement over time. P < 0.05 for the following extraintestinal symptoms: mouth sores,
abnormal liver enzymes, iron deficiency anemia, poor mood, rash, fatigue, arthritis, headache, short stature, and psychiatric disorders.

proximal portion of the small intestine, iron deficiency anemia was
found to be the most common cause for the anemia, although folate
and B12 deficiencies were encountered as well (7). This stresses the
need to be on high alert for CD in any patient with resistant iron
deficiency anemia of an unknown etiology (8,9).
When considering all extraintestinal symptom categories as a
whole, children had a statistically significant higher rate of
improvement as compared to adults. For individual symptoms,
although, statistical significance was only reached for fatigue
likely owing to the small sample size per group, one of the major

120

100

80
%

60

40

20

0
Baseline symptom 6−12 months 13-24 months >24 months
Alopecia Dermatitis herpetiformis Abnormal liver enzymes
Iron deficiency anemia Mouth sores Neuropathy
Arthritis Rash Headache
Psychiatric disorders Arthralgia Fatigue
Myalgia Poor mood Osteoporosis

FIGURE 4. Adult extraintestinal symptoms: rates of improvement over time. P < 0.05 for the following extraintestinal symptoms: dermatitis
herpetiformis, abnormal liver enzymes, iron deficiency anemia, mouth sores, neuropathy, rash, headache, psychiatric disorders, arthralgia,
fatigue, and osteoporosis.

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JPGN  Volume 65, Number 1, July 2017
limitations of this study. The 2 categories in which adults had
slightly greater rates of improvement as compared to children were
abnormal liver enzyme and iron deficiency anemia (although again
no statistical significance was reached). Although 100% of adults
had normalization of their liver enzymes on a strict GFD, a single
child had persistent elevation. This child was later found to have
nonalcoholic fatty liver disease on biopsy explaining her persistent
elevation of transaminases. Our data are in line with the other
studies demonstrating normalization of liver enzymes typically by
the 1-year follow-up on a strict GFD when secondary to celiac
hepatitis (10–12). One should consider further investigation for
other underlying liver conditions when liver enzymes fail to nor-
malize by that time.
Of the patients with extraintestinal symptoms failing to
improve on a GFD, upon further questioning 4% of children and
9% of adults reported that they were not actually strictly adherent to
the diet.
CONCLUSIONS
There are similar rates of extraintestinal manifestations of
CD in children and adults. In children short stature, fatigue, and
headache were most common, whereas anemia, fatigue, headache,
and psychiatric disorders were most common in adults.
Overall, children have high rates of extraintestinal symptom
resolution on a GFD as compared to adults. Reasons for nonresponse
were found to be noncompliance to the GFD or other underlying
comorbidities. Special attention should be given to children with
short stature unresponsive to the GFD as our study showed that
roughly one quarter of these patients had another underlying comor-
bidity. Nonresponse across all categories, although, should prompt
physicians to re-evaluate compliance to the GFD or search for
additional underlying comorbidities in patients with extraintestinal
manifestations of CD failing to respond to a GFD.
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Extraintestinal Manifestations of Celiac Disease
Acknowledgments: The authors are pleased to acknowledge
Diane McKiernan, Research Study Coordinator at the University of
Chicago Celiac Disease Center who provided assistance with data
mining and aided in the production of this manuscript.
REFERENCES
1. Husby S, Koletzko S, Korponay-Szabo IR, et al. European Society for
Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for
the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012;54:
136–60.
2. Fasano A, Catassi C. Clinical practice. Celiac disease. N Engl J Med
2012;367:2419–26.
3. Di Sabatino A, Corazza GR. Coeliac disease. Lancet 2009;373:
1480–93.
4. Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med 2002;346:180–8.
5. Meazza C, Pagani S, Laarej K, et al. Short stature in children with
coeliac disease. Pediatr Endocrinol Rev 2009;6:457–63.
6. Troncone R, Kosova R. Short stature and catch-up growth in celiac
disease. J Pediatr Gastroenterol Nutr 2010;51(suppl 3):S137–8.
7. Halfdanarson TR, Litzow MR, Murray JA. Hematologic manifestations
of celiac disease. Blood 2007;109:412–21.
8. Fayed SB, Aref MI, Fathy HM, et al. Prevalence of celiac disease,
Helicobacter pylori and gastroesophageal reflux in patients with re-
fractory iron deficiency anemia. J Trop Pediatr 2008;54:43–53.
9. Harper JW, Holleran SF, Ramakrishnan R, et al. Anemia in celiac
disease is multifactorial in etiology. Am J Hematol 2007;82:996–1000.
10. Farre C, Esteve M, Curcoy A, et al. Hypertransaminasemia in pediatric
celiac disease patients and its prevalence as a diagnostic clue. Am J
Gastroenterol 2002;97:3176–81.
11. Arslan N, Buyukgebiz B, Ozturk Y, et al. The prevalence of liver
function abnormalities in pediatric celiac disease patients and its
relation with intestinal biopsy findings. Acta Gastroenterol Belg
2005;68:424–7.
12. Bardella MT, Fraquelli M, Quatrini M, et al. Prevalence of hypertran-
saminasemia in adult celiac patients and effect of gluten-free diet.
Hepatology 1995;22:833–6.
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