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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.
predisposed individuals.
Demographics, serologic testing, intestinal biopsies, and extraintestinal  Patients present asymptomatically or with gastroin-
symptoms at presentation, 12, 24, and >24 months were recorded.
testinal and/or extraintestinal symptoms.
Extraintestinal symptoms included abnormal liver enzymes, arthralgia/  The gluten-free diet is the only current treatment for
arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia,
resolving gastrointestinal manifestations, but scarce
stomatitis, myalgias, psychiatric disorders, rashes, seizures, neuropathy,
information is available on its effectiveness in resol-
short stature, delayed puberty, osteoporosis, and infertility.
ving extraintestinal manifestations in children and
Results: A total of 737 patients with biopsy-confirmed celiac disease or
in adults.
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 What Is New
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%)  Children and adults have similar rates of extraintest-
and adults (62%). Short stature (33%), fatigue (28%), and headache (20%) inal manifestations of celiac disease.
were most common in children. Iron deficiency anemia (48%), fatigue (37%),  Children on a strict gluten-free diet show faster and
and headache/psychiatric disorders (24%) were common in adults. Children higher rates of symptom resolution compared
had faster/higher rates of symptom resolution compared with adults. Twenty- with adults.
eight percent of children with unresolved short stature on a GFD were found to  Unresponsive children with short stature must be
have other comorbidities. assessed for 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
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-
(JPGN 2017;65: 75–79) ing in variable degrees of small intestinal inflammation and a wide
range of gastrointestinal and extraintestinal manifestations (1).
Received November 23, 2015; accepted September 19, 2016. Extraintestinal manifestations of CD can include chronic
From the Department of Pediatrics, University of Chicago Medicine fatigue, anemia, osteoporosis, aphthous stomatitis, elevated liver
Comer Children’s Hospital, Chicago, IL, and the yDepartment of enzymes, joint/muscle pain, infertility, epilepsy, and peripheral
Pediatrics, Università degli Studi di Verona, Verona, Italy. neuropathy (2)
Address correspondence and reprint requests to Hilary Jericho, MD, Currently the only effective treatment of CD is strict, lifelong
Division of Gastroenterology, Hepatology, Nutrition, The University of adherence to the gluten-free diet (GFD). This usually results in
Chicago Medicine Comer Children’s Hospital, 5721 S. Maryland Ave,
Chicago, IL 60637 (e-mail: Hjericho@peds.bsd.uchicago.edu).
resolution of small intestinal inflammation (3).
Supplemental digital content is available for this article. Direct URL The aim of the present study was to characterize the preva-
citations appear in the printed text, and links to the digital files are lence of extraintestinal manifestations in children and adults with
provided in the HTML text of this article on the journal’s Web site CD and describe symptom recovery after treatment with a
(www.jpgn.org). strict GFD.
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
PATIENTS AND METHODS
under consideration by the Journal of Pediatric Gastroenterology and
Nutrition. Patients and Data Collection
The authors report no conflicts of interest. We conducted a retrospective review of patient records
Copyright # 2016 by European Society for Pediatric Gastroenterology, contained in a registry (prospectively populated) of children
Hepatology, and Nutrition and North American Society for Pediatric (18 years or younger) and adults (older than 18 years) with CD
Gastroenterology, Hepatology, and Nutrition followed at the University of Chicago between 2002 and 2014.
DOI: 10.1097/MPG.0000000000001420 Before inclusion in the study, a diagnosis of CD was confirmed

JPGN  Volume 65, Number 1, July 2017 75

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

according to the present guidelines (1). The criteria for inclusion in myalgias, psychiatric disorders, rashes, seizures, neuropathy, short
our study were positive serology and Marsh 1–3 findings on biopsy; stature, delayed puberty, osteoporosis, and infertility represented
tissue transglutaminase immunoglobulin A >10 times normal with the most frequent extraintestinal manifestations of CD encountered.
positive endomysial antibody with or without a biopsy; or positive Standardized parameters set forth by the University of Chicago
serology and skin biopsy for dermatitis herpetiformis (DH). In the Medical Center were used to define symptoms with identifiable
case of immunoglobulin A deficiency, deamidated gliadin peptide ‘‘abnormal’’ values such as a total iron <40 and a percentage
immunoglobulin G was used. Exclusion criteria included patients saturation <14 to define iron deficiency anemia, Alt >35 for
lost to follow-up or no data available. All patients had clinical and abnormal liver enzymes, a height >2 standard deviations below
biochemical follow-ups recorded at diagnosis, between 6 and the mean for age and sex for short stature and no secondary sexual
12 months, 12 and 24 months, and at a time point from 24 months maturation or any sign of puberty by the age of 13 years in girls and
onward (2.6 years for children and 2.3 years for adults) and all 14 years in boys for delayed puberty. Psychiatric and neurological
children were evaluated by pediatric gastroenterologists, whereas diagnoses were made by trained professionals in the fields of
all adults were evaluated by adult gastroenterologists. pediatric and adult psychiatry and neurology, respectively. All
other symptoms listed above were based on subjective reports from
Statistical Methods the patients.

McNemar’s chi-square test was used to compare paired Clinical Symptoms and Resolution After
categorical variables. Fisher exact test was used to compare 2 Gluten-Free Diet
categorical variables. Student t test was used to compare groups.
A P value <0.05 was considered significant. Statistical analyses Sixty percent of children and 62% of adults displayed
were performed by using SAS (version 6; SAS institute Inc., extraintestinal manifestations of CD (n ¼ 328, 157 younger than
Cary NC). 18) alone or in combination with gastrointestinal symptoms. Extra-
intestinal manifestations alone were detected in 18% of children and
RESULTS 9% of adults.
Short stature (33%), fatigue (28%), and headache (20%)
General Characteristics of Patients were most common in children and iron deficiency anemia
After a query of our RedCap registry (populated in a pro- (48%), fatigue (37%), and headache/psychiatric disorders (24%)
spective manner by research assistants’ review of physician notes were most common in adults. Short stature and delayed puberty
for explicitly defined variables) we identified 737 pediatric and were only encountered in children, whereas alopecia, infertility,
adult patients (47% children) with the diagnosis of CD. Three neuropathy, and osteoporosis were only encountered in adults
hundred twenty-eight patients (48% children) met our inclusion (Supplemental Digital Content, Figs. 1 and 2, http://links.lww.
criteria and were enrolled into our study (Fig. 1). The mean age com/MPG/A813).
at diagnosis for children was 8.8 years (range 1.3–17.7 years) and Children had greater improvements on a GFD as compared to
40.6 years for adults (range 18.3–75.7). Abnormal liver enzymes, adults for 71% of shared extraintestinal symptoms (P ¼ 0.001),
arthralgia/arthritis, alopecia, fatigue, headache, anemia, stomatitis, although statistical significance was reached for fatigue alone

FIGURE 1. Patient inclusion and exclusion algorithm.

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

100

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P = 0.002
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All categories
40 P = 0.001

30 Pediatric responders

Adult responders
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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 When considering all extraintestinal symptom categories as a
found to be the most common cause for the anemia, although folate whole, children had a statistically significant higher rate of
and B12 deficiencies were encountered as well (7). This stresses the improvement as compared to adults. For individual symptoms,
need to be on high alert for CD in any patient with resistant iron although, statistical significance was only reached for fatigue
deficiency anemia of an unknown etiology (8,9). 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 Extraintestinal Manifestations of Celiac Disease

limitations of this study. The 2 categories in which adults had Acknowledgments: The authors are pleased to acknowledge
slightly greater rates of improvement as compared to children were Diane McKiernan, Research Study Coordinator at the University of
abnormal liver enzyme and iron deficiency anemia (although again Chicago Celiac Disease Center who provided assistance with data
no statistical significance was reached). Although 100% of adults mining and aided in the production of this manuscript.
had normalization of their liver enzymes on a strict GFD, a single
child had persistent elevation. This child was later found to have REFERENCES
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