Case Report: Severe Hypocalcemic Episodes Due to Autoimmune Enteropathy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic disorder, associated with endocrine deficiencies and non-endocrine involvement. Gastrointestinal (GI) manifestations appear in approximately 25% of patients and are the presenting symptom in about 10% of them. Limited awareness among pediatricians of autoimmune enteropathy (AIE) caused by destruction of the gut endocrine cells in APECED patients delays diagnosis and appropriate therapy. We describe an 18-year-old female presenting at the age of 6.10 years with hypoparathyroidism, oral candidiasis and vitiligo. The clinical diagnosis of APECED was confirmed by sequencing the autoimmune regulator-encoding (AIRE) gene. Several characteristics of the disease-Hashimoto's thyroiditis, Addison's disease, diabetes mellitus type 1 and primary ovarian insufficiency-developed over the years. She had recurrent episodes of severe intractable hypocalcemia. Extensive GI investigations for possible malabsorption, including laboratory analyses, imaging and endoscopy with biopsies were unremarkable. Revision of the biopsies and chromogranin A (CgA) immunostaining demonstrated complete loss of enteroendocrine cells in the duodenum and small intestine, confirming the diagnosis of AIE. Management of hypocalcemia was challenging. Only intravenous calcitriol maintained calcium in the normal range. Between hypocalcemic episodes, the proband maintained normal calcium levels, suggesting a fluctuating disease course. Repeated intestinal biopsy revealed positive intestinal CgA immunostaining. The attribution of severe hypocalcemic episodes to AIE emphasizes the need for increased awareness of this unique presentation of APECED. The fluctuating disease course and repeated intestinal biopsy showing positive CgA immunostaining support a reversible effect of GI involvement. CgA immunostaining is indicated in patients with APECED for whom all other investigations have failed to reveal an explanation for the malabsorption.

The Effect of Nutritional Therapy on Bone Mineral Density and Bone Metabolism in Pediatric Crohn Disease.

OBJECTIVES: Both the inflammatory burden of Crohn disease (CD) and corticosteroids have a negative effect on bone density. Exclusive enteral nutrition (EEN) avoids corticosteroids and promotes endoscopic healing. We aimed to explore the effect of nutritional therapy on bone health in pediatric CD. METHODS: This was a planned sub-study of a clinical trial enrolling children with new-onset mild-moderate CD. Children were randomized to either 6 weeks EEN followed by 6 weeks 25% partial enteral nutrition (PEN) or 6 weeks of 50% PEN with a CD exclusion diet followed by 6 weeks of 25% PEN with exclusion diet. Bone formation and resorption were measured at baseline, week 12 and week 24 by serum C-Propeptide of Type I Procollagen (CICP) and type I Collagen N-Telopeptide (NTX), respectively. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) scan at baseline and week 24. RESULTS: Median CICP improved from 130 ng/mL (106-189) at baseline to 223 (143-258) at week 12 and 193 (143-252) at week 24 (P = 0.016 for both, n = 29 children). Median NTX remained unchanged (P = 0.45 and P = 0.45). Thirty-six children had DXA scans performed at diagnosis; 81% and 33% had z scores of <-1 and <-2, respectively. DXA z scores did not improve from baseline (adjusted total body less head [TBLH] BMD -1.62 ±â€Š0.87) to week 24 (-1.76 ±â€Š0.75; P = 0.30, n = 21 with both scans). CONCLUSIONS: Low bone density is common in new-onset mild-moderate pediatric CD. CICP, a sensitive marker of bone formation, improved following dietary intervention but this was not associated with improved BMD.

Dietary Therapies Induce Rapid Response and Remission in Pediatric Patients With Active Crohn's Disease.

BACKGROUND & AIMS: Dietary therapies based on exclusion of usual dietary elements induce remission in children with Crohn's disease (CD), whereas re-exposure induces rebound inflammation. We investigated whether a short trial of dietary therapy, to identify patients with and without a rapid response or remission on the diet (DiRe), can be used to predict success or failure of long-term dietary therapy. METHODS: We collected data from the multicenter randomized trial of the CD exclusion diet (CDED). We analyzed data from 73 children with mild to moderate CD (mean age, 14.2 ± 2.7 y) randomly assigned to groups given either exclusive enteral nutrition (EEN, n = 34) or the CDED with 50% (partial) enteral nutrition (n = 39). Patients were examined at baseline and at weeks 3 and 6 of the diet. Remission was defined as CD activity index scores below 10 and response was defined as a decrease in score of 12.5 points or clinical remission. Inflammation was assessed by measurement of C-reactive protein. RESULTS: At week 3 of the diet, 82% of patients in the CDED group and 85% of patients in the EEN group had a DiRe. Median serum levels of C-reactive protein had decreased from 24 mg/L at baseline to 5.0 mg/L at week 3 (P < .001). Among the 49 patients in remission at week 6, 46 patients (94%) had a DiRe and 81% were in clinical remission by week 3. In multivariable analysis, remission at week 3 increased odds of remission by week 6 (odds ratio, 6.37; 95% CI, 1.6-25; P = .008) whereas poor compliance reduced odds of remission at week 6 (odds ratio, 0.75; 95% CI, 0.012-0.46; P = .006). CONCLUSIONS: For pediatric patients with active CD, dietary therapies (CDED and EEN) induce a rapid clinical response (by week 3). Identification of patients with and without a rapid response to diet might help identify those who, with compliance, will be in clinical remission by week 6 of the diet. ClinicalTrials.gov no: NCT01728870.

Automated Analyzers Are Suited for Diagnosing Celiac Disease Without a Biopsy.

OBJECTIVES: The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2012 guidelines, enabled for the first time, a nonbiopsy approach in the diagnosis of celiac disease (CD). We aimed to prospectively assess 4 tissue-transglutaminase (tTg) IgA assays of 4 random-access analyzers and examine their accuracy in diagnosing CD without a biopsy. METHODS: We enrolled 186 consecutive children referred to upper endoscopy and intestinal biopsy. One group included 109 patients with positive tTg that was referred for suspected CD. Another group included 77 patients with negative tTg referred because of other indications. All participants had a blood sample taken at the time of endoscopy. Samples were tested with 4 tTg IgA assays on automated analyzers and 1 Elisa kit. All intestinal biopsies were evaluated by a local pathologist, a central pathologist, and a CD expert blinded to each other. CD was diagnosed when full agreement was reached. Analytical performance of the assays included precision with controls and samples, lot to lot variation, and carryover. RESULTS: In our cohort, all tested tTg IgA-automated assays showed sensitivities above 98% and specificities above 99%. ROC analysis demonstrated AUC (area under the curve) >0.99 for all 4 analyzers. The positive-predictive values (PPV) were all >0.99 and negative-predictive values (NPV) were >0.97. The Elisa kit had sensitivity of 95%, specificity of 96%, AUC of 0.96, PPV of 0.98 and NPV of 0.93. CONCLUSION: CD can be accurately diagnosed without biopsy based on tTg IgA levels at least 10 times the ULN using the 4 high-volume random-access analyzers used in our study.

Crohn's Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial.

BACKGROUND & AIMS: Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn's disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier. METHODS: We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12. RESULTS: Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P = .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval [CI] 1.68-115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P = .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P = .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34-10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria. CONCLUSION: CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870.

Clinical and Phenotypic Differences in Inflammatory Bowel Disease Among Arab and Jewish Children in Israel.

BACKGROUND: Data on inflammatory bowel disease (IBD) phenotypes among the Arab population in Israel or in the neighboring Arab countries is scarce. AIM: We aimed to assess differences in disease phenotype among Arab and Jewish children living in Israel. METHODS: We performed a retrospective chart review of pediatric IBD cases, which were diagnosed at the Schneider Children's Medical Center and Ha'Emek Medical Center in Israel between 2000 and 2014. Demographic, clinical, and phenotypic variables were compared between Arabs and Jews from Eastern (Sephardic) and Western (Ashkenazi) origin. RESULTS: Seventy-one Arab children with IBD were compared with 165 Ashkenazi and 158 Sephardic Jewish children. Age and gender did not differ between groups. Sephardic and Ashkenazi Jewish Crohn's disease (CD) patients had significantly more stenotic behavior (24 and 26 vs. 5%, p = 0.03) and less fistulzing perianal disease (15 and 11 vs. 31%, p = 0.014) compared with Arab patients. Arab children with ulcerative colitis (UC) had more severe disease at diagnosis compared to Sephardic and Ashkenazi Jews reflected by higher Pediatric UC Activity Index (45 vs. 35 and 35, respectively, p = 0.03). Arab patients had significantly lower proportion of anti-Saccharomyces cerevisiae antibodies positivity (in CD) and perinuclear anti-neutrophil cytoplasmic antibodies positivity (in UC) than both Sephardic and Ashkenazi Jewish children (23 vs. 53 and 65%, p = 0.002 and 35 vs. 60 and 75%, respectively, p = 0.002). CONCLUSION: Arab and Jewish children with IBD differ in disease characteristics and severity. Whether genetic or environmental factors are the cause for these differences is yet to be determined.