What Is Known
- Patients with celiac disease present asymptomatically or with gastrointestinal and/or extra-intestinal symptoms.
- The gluten-free diet is the only current treatment but scarce information is available on its effectiveness in resolving extra-intestinal and gastrointestinal symptoms.
What Is New
- Children and adults have similar rates of gastrointestinal and extra-intestinal manifestations of celiac disease.
- Celiac patients who are adhering to a gluten-free diet show greater rates of gastrointestinal symptom resolution compared with extra-intestinal symptoms.
- Children on a strict gluten-free diet show faster and higher rates of symptom resolution (both gastrointestinal and extra-intestinal) compared with adults.
Celiac disease (CeD) 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 (GI) and extra-intestinal (EI) manifestations (1).
GI and EI manifestations of CeD can include diarrhea, abdominal pain, abdominal distention, anorexia, vomiting, constipation, failure to thrive chronic fatigue, anemia, osteoporosis, aphthous stomatitis, elevated liver enzymes, joint/muscle pain, infertility, epilepsy, and peripheral neuropathy (1,2). Currently the only effective treatment for CeD is strict, lifelong adherence to the gluten-free diet (GFD). This usually results in resolution of small intestinal inflammation (3). However, it has become clear in recent years that many CeD patients continue to suffer from persistent clinical symptoms and experience reduced health-related quality of life despite a strict GFD (4,5).
The aim of the present study was to characterize the prevalence of GI and EI manifestations in children and adults with CeD and describe symptom recovery after treatment with a strict GFD.
Patients and Data Collection
We conducted a retrospective chart review of patients contained in a registry of children (≤18 years of age) and adults (>18 years of age) with CeD followed at the University of Chicago between 2002 and 2015. Before inclusion in the study, a diagnosis of CeD was confirmed according to the present guidelines (6). The criteria for inclusion in our study were positive serology and Marsh 1–3 findings on biopsy or tissue transglutaminase immunoglobulin A more than 10 times the upper limit of normal with positive endomysial antibody with or without a biopsy. In the case of immunoglobulin A deficiency, deamidated gliadin peptide immunoglobulin A was used. Exclusion criteria included patients lost to follow-up or no data available.
Clinical presentation at diagnosis was categorized into GI or EI symptoms or asymptomatic. All of the 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 (average 3.4 years for children and 3.0 years for adults). All of the children were evaluated by pediatric gastroenterologists, and all of the adults were evaluated by adult gastroenterologists. All of the patients were instructed to start a strict GFD with the aid of 1 of our dietitians following their diagnoses.
Non-adherence to the GFD was assessed through patient self-reporting to their primary physicians and evaluation of celiac serologies. Participants were classified as “strictly adherent” if they reported strict adherence during the visit and had continued improvement of their serum transglutaminase 2 (TG2-ab) and/or endomysial (EmA) antibodies. Patient reports to physicians were recorded into our celiac patient registry following their visits and analyzed retrospectively for this study. There was no controlled system in place to further classify the extent to which the patient was truly adherent to the diet.
Duration of symptoms (“no symptoms,” symptoms “<5 years” or symptoms “>5 years”), duration of diet and the presence of other significant comorbidities were also recorded.
Categorical data were described using percentages and quantitative data using medians with range. A P value ≤ 0.05 was considered statistically significant. McNemar's chi-square test was used to compare paired categorical variables whereas a paired t test was used to compare 2 the populations in our study. Statistical analyses were performed using SAS (version 6; SAS Institute Inc, Cary, NC).
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 including symptoms, serologies, and adherence to the GFD) we identified 827 CeD patients (children and adults) of which 554 met inclusion criteria. Eighteen children and 23 adults were lost at follow-up leaving a total of 513 patients that were enrolled into our study. Female-to-male ratios were approximately 2:1 in children and 3:1 in adults (Table 1). Abdominal pain, bloating, constipation, diarrhea, poor weight gain, nausea, reflux and vomiting were the most frequent GI manifestations of CeD encountered. Abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis (DH), alopecia, fatigue, headache, anemia, stomatitis, myalgia, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility were the most frequent EI manifestations encountered. The more commonly encountered comorbidities included thyroid disease (12% children, 6% adults) and food allergy (6% children, 15% adults). Sixteen percent of children and 30% of adults also reported experiencing 1 of the following additional comorbidities: unspecified esophagitis, gastritis, Helicobacter pylori, gastroesophageal reflux, eosinophilic esophagitis, pancreatitis, liver disease, inflammatory bowel disease, lymphocytic and microscopic colitis, lactose intolerance, small intestine bacterial overgrowth, systemic lupus erythematous and Sjogren syndrome, or another collagen vascular disease.
Clinical Symptoms and Resolution After Gluten-free Diet
Seventy-eight percent of children and 91% of adults expressed classical GI symptoms alone or in combination with EI manifestations at the time of their CeD diagnosis. Three percent of adults and 10% of children were asymptomatic and screened because of at-risk relatives.
Abdominal pain (52%), diarrhea (39%), and failure to thrive (37%) were the most commonly reported GI symptoms at the time of diagnosis in children, whereas diarrhea (61%), bloating (56%), and abdominal pain (51%) were most common in adults. Short stature (33%), fatigue (28%), and headache (20%) were the most common EI manifestations in children, whereas iron deficiency anemia (48%), fatigue (37%), and headache/psychiatric disorders (24%) were the most common manifestations in adults (Fig. 1).
All the following data are about manifestations observed at more than 24 months after diagnosis. There were greater rates of improvements in GI versus EI manifestations in both children and adults on a strict GFD with mean improvements of 0.92 and 1.56 (t value = −6.5293 and 2-sided P value of <0.0001), respectively, for children and 1.1 and 1.64 (t value = −5.4206 and 2-sided P value of <0.0001), respectively, for adults (Supplemental Digital Content 1, Fig., http://links.lww.com/MPG/A997). Both GI and EI improvement rates were greater for children as compared to adults (P < 0.001).
Bloating (90%, 75%) diarrhea (90%, 71%), weight loss (89%, 73%), and abdominal pain (81%, 71%) showed the best rates of GI manifestation improvement in children and adults, respectively. Constipation showed the worst rate of improvement for both children and adults at only 74% and 58%, respectively (Supplemental Digital Content 1, Fig., http://links.lww.com/MPG/A997).
Dermatitis herpetiformis, myalgia, stomatitis, delayed puberty, and seizures showed the best rates of EI manifestation improvement in children at 100% with good rates of EI manifestation improvement for iron deficiency anemia and poor mood (84%). Short stature (66%) and psychiatric disorders (56%) showed the worst rates of improvement. Dermatitis herpetiformis, abnormal liver enzymes, and seizure showed the best rates of EI manifestation improvement in adults at 100% with good rates of EI manifestation improvement for iron deficiency anemia (85%). Myalgia and poor mood (50%) showed the worst rates of improvement (Supplemental Digital Content 2, Fig., http://links.lww.com/MPG/A998).
Diet and Refractory Celiac Disease
When evaluating all pediatric and adult patients within the duration of the study period, only 8% of pediatric patients reported non-adherence to the GFD as compared to 12% of adults. Twenty-five percent of these non-adherent pediatric patients reported ongoing GI manifestations whereas 33% reported ongoing EI manifestations (62% total). Twenty-eight percent of these non-adherent adult patients reported ongoing GI manifestations whereas 50% reported ongoing EI manifestations (70% total).
Even despite patient reports of strict adherence to the GFD, 34% of pediatric patients and 52% of adult patients still reported 1 or more ongoing GI or EI manifestations. Nonadherence to the GFD was significantly associated with failed response (P = 0.0060). Four adults (1.5%) developed refractory CeD whereas no child did.
Figure 2 shows the proportion of CeD patients reporting symptoms with regard to adherence to the GFD. Patients have been categorized into 1 of 3 groups including Patients strictly adherent to the GFD, patients intermittently strictly adherent to the GFD, or patients with non-adherence to the GFD. Supplemental Digital Content 3 and 4, Figs. 3 and 4, http://links.lww.com/MPG/A999 and http://links.lww.com/MPG/A1000 show the prevalence of persistent GI and EI symptoms in adherent versus non-adherent adults and children.
Other Variables: Sex, Age, and Other Diseases
There were higher rates of all manifestations in girls as compared to boys (odds ratio = 1.68, P value = 0.1457), with the exception of myalgia in children. For adults, boys showed better rates of both GI and EI manifestation improvement as compared to adult girls. Pediatric boys showed better rates of EI symptoms resolution whereas pediatric girls showed better rates of GI symptom resolution. As a whole, boys showed greater rates of EI and GI manifestation improvements as compared to girls (P = 0.0074). Younger patients, regardless of sex, had greater rates of improvement for both GI and EI manifestations as compared to older patients (P < 0.0001).
Patients with a longer duration of manifestations before their CeD diagnosis (>5 years) were found to have worse rates of symptom resolution on a GFD (P = 0.0004). Conversely, duration of adherence to the GFD was not associated with worse rates of symptom resolution (P = 0.3442). Patients with a family history of CeD had better rates of symptom resolution on a GFD (P = 0.0001).
Thirty-seven percent of children and 73% of adults were found to have comorbidities. These included thyroid disease, type 1 diabetes, food allergy, unspecified esophagitis, gastritis, Helicobacter pylori, gastroesophageal reflux, eosinophilic esophagitis, pancreatitis, liver disease, inflammatory bowel disease, lymphocytic and microscopic colitis, lactose intolerance, small intestine bacterial overgrowth, systemic lupus erythematous and Sjogren syndrome, or another collagen vascular disease. No comorbidity was associated with worse rates of symptom resolution (Table 2).
Although CeD primarily affects the gut, the clinical manifestations of the disease are incredibly diverse with many GI and EI manifestations possible (7).
To our knowledge, the present study is the first comparing the prevalence and resolution of both GI and EI manifestations of CeD on a GFD in pediatric and adult celiac populations in addition to investigating possible predictors of poor symptom resolution despite strict adherence to a GFD.
Similar to other studies, our series confirmed that the most common GI manifestations of CeD were diarrhea in younger children and abdominal pain in older children (8). For EI manifestations, short stature and failure to thrive were most common in younger children whereas headache and fatigue were most common in older children (3,9). For adults with CeD, diarrhea and bloating were the most common GI manifestations whereas iron deficiency anemia was the most common EI manifestation (10–13). Girls were more likely than boys to experience both GI and EI manifestations (3:1) (14,15). The reason for this discrepancy is still undetermined, but questioned to be related to differences in sex hormones and genetics (16,17). For CeD children on a strict GFD, the best rates of GI symptom improvement were seen for bloating, diarrhea, weight loss, and abdominal pain and DH, myalgia, aphthous stomatitis, and delayed puberty for EI symptoms improvement. For CeD adults on a strict GFD, the best rates of GI symptom improvement were seen with bloating, weight loss, abdominal pain and diarrhea and DH, abnormal liver enzymes, and seizures for EI symptom improvement. Constipation showed poor rates of improvement in children and adults (58% and 52%, respectively) likely explained by the already recognized constipating nature of the GFD (18).
Few studies have analyzed GI and EI symptom resolution in children as compared to adults (8,19,20). In our current study, we have shown that both children and adults with CeD on a strict GFD show greater and faster rates of GI symptom improvement as compared to EI symptom improvement and that children have greater rates of GI and EI symptom resolution as compared to adults. This may be secondary to a more complex mechanism leading to EI symptoms, as compared to GI symptoms, requiring more time for reversal.
We additionally investigated other factors contributing to poor symptom resolution despite strict adherence to the GFD. We found that sex had a statistically significant impact on symptom recovery with boys showing greater rates of symptom resolution as compared to girls in both the pediatric and adult populations (20). Longer durations of symptoms before the diagnosis of CeD predisposed a patient to poor symptom resolution, which may be explained by alterations to the gut-brain axis leading to a chronic cycle of pain (21,22). On the contrary, a positive family history of CeD was associated with improved rates of symptom resolution, likely secondary to the more supportive and understanding environment provided by a family who is already knowledgeable about the disease. Duration of the diet and our examined comorbidities did not appear to be statistically related to a patient's rate of symptom resolution. Not too surprisingly, patients with strict adherence to the GFD experienced greater fates of GI and EI symptom resolution at 24 months as compared to those not strictly adherent.
The retrospective nature of our study was an obvious limitation, preventing us from using standardized questionnaires to evaluate both the degree of strictness to the GFD and for gluten contamination. Follow-up, prospective studies would have the advantage of more closely scrutinizing these aspects.
On a strict GFD, children report greater rates of both GI and EI symptom resolution as compared to adults with greater rates of improvement in GI as compared to EI symptoms. Best rates of improvement were seen with bloating, diarrhea, weight loss, DH, myalgia, and aphthous stomatitis in children and bloating, weight loss, abdominal pain, DH, abnormal liver enzymes and seizure for adults. Boys had greater rates of symptom improvement as compared to girls. Longer duration of symptoms before diagnosis and poor adherence to the GFD predisposed a patient to poor symptom resolution, whereas a positive family history of CeD was associated with improved rates of symptom resolution. Duration of the diet and our examined comorbidities did not appear to be statistically related to a patient's rate of symptom resolution. Patients who were not strictly adherent to the GFD showed worse rates of symptom improvement at 24 months as compared to those who were. These findings emphasize the need for early recognition of CeD and close attention to diet adherence as these will aid in the most positive outcomes for the patient.
The authors are pleased to acknowledge Diane McKiernan, Research Study Coordinator at the University of Chicago Celiac Disease Center and Wroblewski, Kristen, Biostatistician at the University of Chicago who provided assistance with data mining and aided in the production of this manuscript.
1. Guandalini S, Assiri A. Celiac disease: a review. JAMA Pediatr
2. Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. Gut
3. Di Sabatino A, Corazza GR. Coeliac disease. Lancet
4. Abdulkarim AS, Burgart LJ, See J, et al. Etiology of nonresponsive celiac disease: results of a systematic approach. Am J Gastroenterol
5. Murray JA, Watson T, Clearman B, et al. Effect of a gluten-free diet on gastrointestinal
symptoms in celiac disease. Am J Clin Nutr
6. 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
7. Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med
8. Khatib M, Baker RD, Ly EK, et al. Presenting pattern of pediatric celiac disease. J Pediatr Gastroenterol Nutr
9. McGowan KE, Castiglione DA, Butzner JD. The changing face of childhood celiac disease in North America: impact of serological testing. Pediatrics
10. Rampertab SD, Pooran N, Brar P, et al. Trends in the presentation of celiac disease. Am J Med
11. Harper JW, Holleran SF, Ramakrishnan R, et al. Anemia in celiac disease is multifactorial in etiology. Am J Hematol
12. Rodrigo-Saez L, Fuentes-Alvarez D, Perez-Martinez I, et al. Differences between pediatric and adult celiac disease. Revista espanola de enfermedades digestivas
13. Jericho H, Sansotta N, Guandalini S. Extra-intestinal
manifestations of celiac disease: effectiveness of the gluten free diet. J Pediatr Gastroenterol Nutr
2016; Epub ahead of print.
14. Green PHR, Stavropoulos SN, Panagi SG, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol
15. Hauser W, Stallmach A, Caspary WF, et al. Predictors of reduced health-related quality of life in adults with coeliac disease. Aliment Pharmacol Therap
16. Amur S, Parekh A, Mummaneni P. Sex differences and genomics in autoimmune diseases. J Autoimmun
17. Nussinovitch U, Shoenfeld Y. The role of gender and organ specific autoimmunity. Autoimmun Rev
18. Farnetti S, Zocco MA, Garcovich M, et al. Functional and metabolic disorders in celiac disease: new implications for nutritional treatment. J Med Food
19. Paarlahti P, Kurppa K, Ukkola A, et al. Predictors of persistent symptoms and reduced quality of life in treated coeliac disease patients: a large cross-sectional study. BMC Gastroenterol
20. Pulido O, Zarkadas M, Dubois S, et al. Clinical features and symptom recovery on a gluten-free diet in Canadian adults with celiac disease. Can J Gastroenterol
21. Knowles CH, Aziz Q. Basic and clinical aspects of gastrointestinal
22. Sharma A, Lelic D, Brock C, et al. New technologies to investigate the brain-gut axis. World J Gastroenterol