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Mucosal Healing in Children With Treated Celiac Disease

Ghazzawi, Youssef*; Rubio-Tapia, Alberto; Murray, Joseph A.; Absah, Imad*

Journal of Pediatric Gastroenterology and Nutrition: August 2014 - Volume 59 - Issue 2 - p 229–231
doi: 10.1097/MPG.0000000000000390
Original Articles: Gastroenterology

Objectives: Limited data suggest complete mucosal healing in treated children with celiac disease (CD), but recent data from adult endoscopic biopsies have shown substantial numbers with persistent mucosal injury. We aimed to assess the rate of mucosal healing and indications for repeat small bowel (SB) biopsy in children with CD.

Methods: We retrospectively reviewed records of children (ages 1–18 years) with CD who underwent a second SB biopsy. All of the children were seen at Mayo Clinic (Rochester, MN) from January 1997 through June 2013.

Results: Forty children were identified (14 boys); average age at diagnosis was 8.5 years. Indications for second SB biopsy were abdominal pain (n = 20), diarrhea (n = 7), constipation (n = 5), non–celiac-related concern (n = 2), follow-up (n = 5), and persistent serology (n = 1). Average time between biopsies was 24 months (range 4–120 months). Histology on the second biopsy showed complete healing (n = 25), intraepithelial lymphocytes (n = 9), and persistent villous atrophy (n = 6). Of these, 3 patients had partial villous atrophy and 3 had with complete villous atrophy. Persistent villous atrophy was observed in 2 of 20 patients with abdominal pain and 1 of 7 with diarrhea. All of the patients with persistent constipation (n = 5) had complete resolution.

Conclusions: Mucosal healing in children with CD may not be complete as previously assumed. Abdominal pain was the most common indication for repeating the SB biopsy. Persistence of abdominal pain, diarrhea, and constipation was poorly associated with persistence of mucosal injury.

*Division of Pediatric Gastroenterology and Hepatology

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

Address correspondence and reprint requests to Imad Absah, MD, Division of Pediatric Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail:

Received 8 October, 2013

Accepted 27 March, 2014

The authors report no conflicts of interest.

Celiac disease (CD) is a common immune-mediated disease that results in small bowel (SB) mucosal injury after consuming gluten-containing cereals such as wheat, barley, and rye (1). The only available affective treatment is a lifelong gluten-free diet (GFD), resulting in normalizing antibodies and healing of the SB mucosa in patients with CD (2). In most patients clinical response is observed in few weeks after starting a GFD (3); however, achieving a complete clinical response with a GFD is not always associated with mucosal recovery (4,5). Poor correlation between clinical symptoms and mucosal injury has been reported, with some asymptomatic patients with CD with severe mucosal damage (6).

Recent data from treated adults with CD suggest that the rate of SB mucosal recovery is somewhat slow and variable, and it may require >2 years, reaching a mucosal healing rate of 66% after 5 years on a strict GFD (7–9). Persistent villous atrophy compared with mucosal healing was associated with an increased risk for lymphoproliferative disorders (10). Also, persistent SB mucosal injury may increase the risk of severe complications and death in patients with CD, even in the absence of symptoms, so confirming mucosal recovery after starting GFD may be clinically indicated (11,12).

Children with CD generally are presumed to have nearly complete mucosal healing (up to 95%) within 24 months after starting a GFD (13); however, the reported high rates of mucosal healing in children are from old reports (14,15), when Crosby capsules were used to obtain SB biopsy specimens likely from proximal jejunum or from adult studies with a small number of children with CD. Clinical factors associated with either mucosal healing or persistent mucosal damage are unknown. We conducted this retrospective study to assess the rate of mucosal healing and the indications for repeating SB biopsies in treated children with CD.

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The study protocol was approved by the institutional review board of the Mayo Clinic. Retrospective data review of the Mayo Clinic electronic medical record was conducted.

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We identified all of the pediatric patients with SB biopsy-proven CD who underwent a repeat endoscopy with second SB biopsy from January 1997 through June 2013. Patients with other underlying disease such as inflammatory bowel disease, bacterial overgrowth, giardiasis, intestinal lymphangiectasia, hypogammaglobulinemia, and eosinophilic enteritis/food allergies were excluded. None of the included patients were diagnosed as having Helicobacter pylori infection during the time of the study.

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Clinical Manifestations and Histologic Results

Clinical manifestation at the time of first and second SB biopsies were recorded and compared. Pathologic reports were reviewed by 1 author (Y.G.) to document the degree of villous injury on the first and second SB biopsy specimens. Histologic assessment was performed using a modified Marsh classification as follows: 0 = normal SB; 1 = normal villi with increased intraepithelial lymphocytes (>25 lymphocytes per 100 epithelial cells); 2 = normal villi with crypt hyperplasia; 3A = mild villous atrophy; 3B = subtotal villous atrophy; and 3C = total villous atrophy (16).

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Statistical Analysis

Data were summarized with descriptive statistics. Continuous variables were reported as mean (SD).

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In total, 222 children were diagnosed as having CD during the study period based on suggestive symptoms, positive anti–tissue transglutaminase antibodies immunoglobulin A (anti-TTG IgA) at time of diagnosis and confirmed by SB biopsies. Of these, 40 patients (18%) had a repeat endoscopy and second SB biopsy. Fourteen patients (35%) were boys; mean (SD) age at diagnosis was 8.5 (4.5) years. Many of these patients reported multiple symptoms at initial presentation. The symptoms most commonly reported at the time of diagnosis were abdominal pain (n = 28 [70%]), diarrhea (n = 11 [28%]), constipation (n = 5 [13%]), abdominal distension (n = 4 [10%]), and failure to thrive (n = 3 [8%]). The reported degree of mucosal injury on the first biopsy was Marsh 1 (n = 4 [10%]), Marsh 3B (n = 26 [65%]), and Marsh 3C (n = 10 [26%]). Patients with Marsh 1 were diagnosed as having CD based on positive anti-TTG IgA titers and suggestive gastrointestinal symptoms of CD that improved (both symptoms and anti-TTG IgA) on the GFD. Adherence to GFD and exclusion of gluten exposure was assessed by a strict diet assessment by an experienced CD dietitian.

The indication for repeating the SB biopsy in those 40 patients was persistence of symptoms on strict GFD in 32 (80%) patients, such as abdominal pain in 20 patients, diarrhea in 7, and constipation in 5; asymptomatic patients who either requested a follow-up SB biopsy for concern about the mucosal healing or were following the adult practice because they had an adult family member with CD who had a repeat SB biopsy in 5 (13%) patients; non–celiac-related concern (suspicion of eosinophilic esophagitis) in 2; and persistently positive serology in 1. Table 1 compares symptoms and pathologic findings at the time of first and second biopsies.



Mean (SD) time between the first and second biopsies was 24 (22) months (range 4–120 months). Thirty-four patients (85%) had resolution of the villous atrophy: 25 (63%) had normal SB mucosa and 9 (23%) were Marsh 1. Six (15%) of 40 patients had persistent villous atrophy. Three patients had Marsh 3B and 3 had Marsh 3C. One of the patients with Marsh 3B and abdominal pain was found to have persistent gluten exposure and was excluded; the other 2 patients with Marsh 3B had improved their histology (improved from 3C to 3B) and diarrhea for 18 months between the first and second SB biopsies. The remaining 3 patients had Marsh 3C despite being on a strict GFD. The indications for repeating endoscopy in these patients were nonspecific/nonmalabsorptive abdominal pain (n = 2) and follow-up biopsy (n = 1). After excluding the patient with gluten exposure and patients with Marsh 1 on the repeated SB biopsy, we found that the mucosal healing rate in this selected group of children with treated CD was 25 of 39 (64%) after an average of 24 months on GFD.

Most of the children with persistent or relapsed nonspecific clinical symptoms experience some clinical improvement after starting the GFD. Repeating the SB biopsy did not reveal persistence of villous atrophy in most of these children. Only 2 of 20 patients (10%) with abdominal pain as an indication for the second SB biopsy had persistent villous atrophy with negative serology. All 5 patients with persistent constipation had complete resolution (4 had a normal SB, 1 had Marsh 1). One patient of the 7 with diarrhea as the indication for the second biopsy had persistent villous atrophy with negative serology. Table 2 shows the degree of mucosal injury for patients with persistent symptoms.



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This study had several notable findings. First, the mucosal healing rate was 64% in a selected group of treated children with mean time for follow-up biopsy of 24 months. Second, abdominal pain was the most common indication for repeating SB biopsy in treated children with CD. Third, persistence of nonspecific symptoms in these patients was poorly associated with presence of villous atrophy on the follow-up biopsy.

In children with CD, complete healing (Marsh 0) of mucosal injury had been presumed to occur within 6 to 12 months after starting a GFD (17). On the contrary, Wahab et al (13) reported a mucosal healing rate of 65% at 2 years and a long-term rate of 89.9% in adult patients with complete villous atrophy. Even slower rates of mucosal healing were reported by our colleagues at Mayo Clinic in adult patients with CD. They also reported a trend toward an association between achievement of mucosal recovery and a reduced rate of all-cause mortality (18). This new insight about poor mucosal healing in adults with CD, as well as the risk of long-term consequences, raises the concern about the accuracy of the presumption of mucosal healing in children with CD. In 1 commonly cited 1986 study, Shmerling and Franckx (14) assessed the rate of SB mucosal injury relapse with a gluten challenge rather than assessing the mucosal healing on a GFD. In contrast, Congdon et al (19) reported an incomplete healing rate of 80% after 1 year on a GFD, which is closer to the recently reported rates in adults with CD.

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines suggested that in children and adolescents with signs or symptoms suggestive of CD and high anti-TTG IgA titers with levels >10 times the upper limit of normal, the likelihood for villous atrophy (Marsh 3) is high. In this situation, further laboratory testing such as endomysial immunoglobulin A antibodies or human leukocyte antigen-DQ2 and -DQ8 can be performed to make the diagnosis of CD without SB biopsies (20). The increased risk of complications in patients with persistent villous atrophy, however, warrants a better assessment of the true mucosal healing process in treated children with CD before we apply the new the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition criteria on all children with CD.

Adult data suggested poor correlation between the degree of mucosal injury and clinical manifestations in patients with CD (21–23). Similarly, we found poor association between the degree of villous atrophy and symptom persistence. Knowing that the risk of functional abdominal pain is similar between children with CD and controls (24), it is possible that our patients, who had persistent nonspecific abdominal pain despite identifying and treating their CD, had functional abdominal pain to start with and CD was an incidental finding. Another possible explanation is that CD causes persistent visceral nerve injury, similar to what is found in postinfectious irritable bowel syndrome pain (25). We cannot generalize this finding because of the small sample size. The decision of repeating the scope in children with CD and persistent symptoms should be made based on each unique case presentation. Repeating SB biopsy may have a low yield in children with nonspecific symptoms (absence of malabsorptive findings or alarm signs) if celiac serology has normalized. Again, a prospective study with lifestyle and pain assessment questionnaires at the time of diagnosis and long-term follow-up would be helpful in assessing the presence of post-CD pain in children who have pain as the primary symptom.

The major limiting factors of this study are its retrospective nature and the fact that indications for the second SB biopsy in most of the cases were reasons other than follow-up evaluation (selection bias). Despite these limitations, we found that 64% of patients who adhered to a GFD for an average of 24 months had complete mucosal recovery. Even with the increased risk associated with persistent mucosal damage in treated patients with CD, justifying repeating an invasive procedure such as SB biopsy in children may be an ethical dilemma; on the one hand, there is the risk of invasive procedure in children and, on the other hand, there is the risk of children without symptoms and with persistent villous atrophy. Results from a prospective multicenter study may help determine the need and importance of repeating the SB biopsy in asymptomatic children with treated CD to assess for mucosal healing.

In conclusion, the rate of mucosal healing of symptomatic treated children with CD was not universal and is close to the reported healing rate in adults, and the persistence of abdominal pain, diarrhea, and constipation did not correlate with the persistence of mucosal injury in this select group of patients.

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celiac; gluten; mucosa; pain; villous atrophy

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