What Is Known
- Celiac disease is a complex autoimmune disease, triggered by the ingestion of gluten in genetically predisposed individuals.
- Patients present asymptomatically or with gastrointestinal 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 resolving extraintestinal manifestations in children and in adults.
What Is New
- Children and adults have similar rates of extraintestinal 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.
Celiac disease (CD) is a complex autoimmune disease, triggered 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 resulting 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 prevalence 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 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 prospective 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, 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.
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FIGURE 1: Patient inclusion and exclusion algorithm.
Clinical Symptoms and Resolution After Gluten-Free Diet
Sixty percent of children and 62% of adults displayed extraintestinal manifestations of CD (n = 328, 157 younger than 18) alone or in combination with gastrointestinal symptoms. Extraintestinal 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, https://links.lww.com/MPG/A813).
Children had greater improvements on a GFD as compared to adults for 71% of shared extraintestinal symptoms (P = 0.001), although statistical significance was reached for fatigue alone (P = 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 herpetiformis and seizure improved on a GFD as did all children with delayed puberty. Patients with DH did not receive dapsone or other pharmacologic therapies.
FIGURE 2: Extraintestinal symptom response rates on a gluten-free diet (GFD): pediatrics versus adults.
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, respectively, 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.
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.
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.
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 improvements in their extraintestinal symptoms.
There were no statistically significant differences between the age at diagnosis (P = 0.23) and sex (P = 0.49) between responders and nonresponders.
DISCUSSION
Although CD primarily affects the gut, the clinical manifestations of the disease are incredibly diverse with many extraintestinal 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 extraintestinal 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 inflammatory 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 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 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 normalize 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 comorbidity. 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.
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.
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