Edward J. Hoffenberg

Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in children and adolescents with gastrointestinal symptoms, dermatitis herpetiformis, dental enamel defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia and in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin (Ig)A deficiency and first degree relatives of individuals with celiac disease. The Celiac Disease Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnosis and treatment of pediatric celiac disease based on an integration of a systematic review of the medical literature combined with expert opinion. The Committee examined the indications for testing, the value of serological tests, human leukocyte antigen (HLA) typing and histopathology and the treatment and monitoring of children with celiac disease. It is recommended that children and adolescents with symptoms of celiac disease or an increased risk for celiac disease have a blood test for antibody to tissue transglutaminase (TTG), that those with an elevated TTG be referred to a pediatric gastroenterologist for an intestinal biopsy and that those with the characteristics of celiac disease on intestinal histopathology be treated with a strict gluten-free diet. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition on the diagnosis and treatment of celiac disease in children and adolescents.

Rotavirus Infection Frequency and Risk of Celiac Disease Autoimmunity in Early Childhood: A Longitudinal Study

OBJECTIVE:Few studies have assessed the role of specific gastrointestinal infections in celiac disease. We investigated whether increased frequency of rotavirus infection, a common cause of gastrointestinal infection and inflammation, predicts increased risk of celiac disease autoimmunity.METHODS:A cohort of 1,931 children from the Denver metropolitan area who carried celiac disease human leukocyte antigen (HLA) risk alleles were followed from infancy for development of celiac disease autoimmunity, defined as positivity at two or more subsequent clinic visits for tissue transglutaminase (tTG) autoantibodies measured using a radioimmunoassay with human recombinant tTG. Blood samples were obtained at ages 9, 15, and 24 months, and annually thereafter. Rotavirus antibodies were assayed using an indirect enzyme immunoassay in serial serum samples from each case and two matched controls. Frequency of infections were estimated by the number of increases (>2 assay coefficient of variation) in rotavirus antibody between clinic visits.RESULTS:Fifty-four cases developed celiac disease autoimmunity at a median age of 4.4 yr. Thirty-six had an intestinal biopsy, of which 27 (75%) were positive for celiac disease. Frequent rotavirus infections predicted a higher risk of celiac disease autoimmunity (compared with zero infections, rate ratio 1.94, 95% confidence interval [CI] 0.39–9.56, for one infection and rate ratio 3.76, 95% CI 0.76–18.7, for ≥2 infections, rate ratio for trend per increase in number of infections = 1.94, 95% CI 1.04–3.61, p = 0.037). The result was similar after adjustment for gender, ethnic group, maternal education, breast-feeding, day-care attendance, number of siblings, season of birth, and number of HLA DR3-DQ2 haplotypes.CONCLUSIONS:This prospective study provides the first indication that a high frequency of rotavirus infections may increase the risk of celiac disease autoimmunity in childhood in genetically predisposed individuals.

A prospective study of the incidence of childhood celiac disease

OBJECTIVES To estimate the frequency of celiac disease (CD) in children in the general population of Denver, Colorado. STUDY DESIGN From 22,346 newborns characterized as expressing 0, 1, or 2 HLA-DR3(DQB1*0201) alleles, 987 were selected for a prospective stratified cohort study. Participants were followed for as long as 7 years with serial testing for serum IgA anti-transglutaminase antibodies and for evidence of CD (intestinal mucosal changes or persistent seropositivity). RESULTS Of 40 children with at least one positive serologic test, 19 had evidence of CD (10 by biopsy, 9 by persistent seropositivity). Those expressing 0, 1, or 2 HLA-DR3 alleles had, respectively, 0.3% (95% CI, 0.0-2.7), 3.4% (3.0-11.7), and 3.2% (1.0-11.0) risk for evidence of CD by age 5 years. The adjusted risk estimate for evidence of CD by age 5 years for the Denver general population was 0.9% (0.4-2.0), or 1 in 104 (1:49-221). After adjusting for number of HLA-DR3 alleles expressed, risk was higher in females: RR=3.34 (1.00-10.9, P=.048). Evidence of CD was not observed before age 2.6 years. CONCLUSIONS Celiac disease may affect 0.9% of Denver children by 5 years of age. Children positive for the HLA-DR3 allele and females appear to be at increased risk.

Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy

OBJECTIVE To determine the outcome, in index patients followed at an American Center, of syndromic paucity of interlobular bile ducts (sPILBD; Alagille syndrome), with onset of cholestasis in infancy. DESIGN Cohort. SETTING Regional referral center for infants and children with liver disease. RESULTS During the past 10 years, 26 unrelated children with sPILBD were identified. Fifteen (58%) are alive without liver transplantation at a median age of 12.1 years. Three (11%) died, all before 2 years of age. Eight patients (31%) underwent liver transplantation at a median age of 6.5 years; all eight are alive a median 5.4 years after transplantation. The most common factors contributing to the decision for transplantation were bone fractures, pruritus, and severe xanthoma. The predicted probability of reaching 19 years of age without transplantation is about 50%; however, with transplantation, the predicted probability of long-term survival is 87%. Of 26 patients 4 (15%) have had significant central nervous system disease, and two of them have died of intracranial hemorrhage. Of the four patients who underwent cholecystoportostomy or portoenterostomy, three required liver transplantation. CONCLUSIONS Children with sPILBD identified in infancy because of cholestasis have a 50% probability of long-term survival without liver transplantation, a worse prognosis than other follow-up studies have reported. In selected patients, liver transplantation provides the opportunity for long-term survival with improved quality of life. Patients with sPILBD are at risk of having intracranial hemorrhage.

Serologic testing for inflammatory bowel disease

OBJECTIVES To determine the accuracy of anti-neutrophil cytoplasmic antibodies (ANCAs) and anti-Saccharomyces cerevisiae antibodies (ASCA) in distinguishing patients with inflammatory bowel disease from patients with other disorders, seen in a pediatric gastroenterology clinic setting, and in distinguishing ulcerative colitis (UC) from Crohns disease (CD). STUDY DESIGN Serum samples from 120 children with new or established diagnoses of UC (n = 25) or CD (n = 20) and control children (n = 74) were analyzed in blinded fashion for the presence of IgG ANCAs and IgA and IgG ASCA. RESULTS The highest sensitivity for detecting inflammatory bowel disease, 71%, was achieved by using ANCAs and ASCA together. The best test for UC was ANCAs, which had a sensitivity of 80%. However, the ANCA pattern characteristic of UC, perinuclear ANCAs eliminated by DNAse, had a sensitivity of 60%. High-titer ANCAs were specific for UC, whereas ASCA were specific for CD. CONCLUSIONS Testing for ANCAs and ASCA together did not achieve sensitivity necessary for population screening. However, ANCAs and ASCA may be helpful in evaluating children suspected of having inflammatory bowel disease and in distinguishing UC from CD.

A Report on the International Transglutaminase Autoantibody Workshop for Celiac Disease

OBJECTIVES:Measurement of transglutaminase autoantibodies (TGAA) is considered to be the most efficient single serologic test for celiac disease (CD) by the American Gastroenterological Association Institute. We hypothesized that a large international collaborative effort toward improving and standardizing TGAA measurement is both feasible and necessary. The primary aim of this workshop is to compare TGAA assays among various research and clinical laboratories to examine assay concordance and improve (and eventually standardize) the TGAA assay.METHODS:A total of 20 laboratories (5 commercial laboratories, 15 research and clinical laboratories) participated that included enzyme-linked immunosorbent assay (ELISA) and radiobinding assays. A total of 150 serum samples were distributed to each laboratory, with each laboratory receiving an equal aliquot that was coded and blinded, composed of 100 healthy control sera and 50 CD sera.RESULTS:Laboratory sensitivity ranged from 69% to 93% and specificity ranged from 96% to 100%. By receiver operator characteristic analysis, the area under the curve (C index) ranged from 0.9488 to 0.9904. When analyzing for linear correlation, r-squared was as high as 0.8882 but as low as 0.4244 for the celiac samples between different laboratories performing ELISA.CONCLUSIONS:This transglutaminase autoantibody workshop allows for larger-scale international participation for the purposes of improving and eventually standardizing the TGAA assay with subsequent workshops.

Natural history of antibodies to deamidated gliadin peptides and transglutaminase in early childhood celiac disease.

Introduction: Gliadin proteins play a key role in the pathogenesis of celiac disease; however, as a screen for celiac disease, anti-gliadin antibody testing has been replaced by the more sensitive and specific serological assays for transglutaminase autoantibodies (TGAA). A new generation of anti-gliadin antibody assays has been developed to detect synthetic, deamidated homologous gliadin peptides (DGP) with high sensitivity and specificity. Methods: Sera were collected prospectively from children with an increased risk for celiac disease as part of an ongoing study at Denver, and studied for the development of celiac autoimmunity. We investigated the high-performance DGP antibody assay in 50 TGAA-positive children both before the development of celiac autoimmunity and following the institution of a gluten-free diet to determine the relationship of DGP antibodies to TGAA. TGAA were measured by an in-house radioassay. Results: DGP antibodies and TGAA parallel each other over the period of years children were studied. DGP antibodies resolved sooner than TGAA in subjects on a gluten-free diet. DGP antibodies appeared earlier than TGAA in 9 children. Conclusions: Measuring DGP antibodies may be more useful than TGAA in monitoring children on a gluten-free diet. DGP antibodies can precede the appearance of TGAA in some at-risk children.

Variation in care in pediatric Crohn disease.

Objectives:Variation in medical care can be a barrier to improving clinical outcomes. We aim to describe the variation in care of Crohn disease as provided by a broad sample of pediatric gastroenterologists. Methods:Two hundred forty-six Crohn disease patients of 93 pediatric gastroenterologists from 48 practice sites starting treatment with either thiopurine or infliximab were studied. We assessed variation in diagnostic testing that had been performed to establish the diagnosis of Crohn disease and to assess the phenotype, extent, and severity of disease. We also assessed variation in initial thiopurine and infliximab dosage and in nutritional therapy. Results:Diagnostic studies in which care was uniform included complete blood count, performed in 100% of patients, erythrocyte sedimentation rate and colonoscopy in 96%, and upper endoscopy in 89%. However, imaging of the small bowel had not been performed in 19%, and a stool test for pathogens had not been performed in 29%. Thiopurine methyltransferase (TPMT) had been measured in 61% of patients before treatment with a thiopurine; in 85%, TPMT was normal. Nonetheless, even when TPMT was normal, 40% of patients received an initial dose of thiopurine that was lower than recommended. Testing for tuberculosis before initiating treatment with infliximab was not performed in 30%. In addition, 36% of severely underweight patients were not receiving a multivitamin supplement, supplemental formula, or tube feeding. Conclusions:There is variation in diagnostic and therapeutic interventions in the management of pediatric Crohn disease, and gaps exist between recommended and actual care.

Symptomatic Colonic Polyps in Childhood: Not So Benign

BACKGROUND The clinical spectrum of symptomatic polyps and the frequency of familial polyposis is not well defined in children. In the present study, a series of children with juvenile polyposis coli (JPC) and non-JPC polyps were studied. METHODS Children with symptomatic colonic polyps and negative family history of polyps were ascertained by review of endoscopic records. Juvenile polyposis coli was defined as 10 or more juvenile polyps or any juvenile polyp in a relative of an index case of JPC. Polyps were tested for Ki-ras mutations, p53 overexpression, and aneuploidy. RESULTS Seventy-eight children (age range, 0.4-18 years) were identified, all evaluated for lower gastrointestinal bleeding. Nine (12%) had JPC, 66 (84%) had isolated juvenile polyps, and 3 (4%) had other types of polyps. The JPC and non-JPC groups were similar in age (p = 0.4) and symptom duration (p = 0.3). The JPC group had more polyps (p = 0.0001), and greater likelihood of anemia (p = 0.01), polyps with adenomatous change (p = 0.03), and right-colon polyps (p = 0.001). In three of eight JPC families, polyps were identified in asymptomatic first-degree relatives. No abnormalities in Ki-ras, p53, or aneuploidy were identified. CONCLUSIONS Juvenile polyposis coli is common in children with symptomatic polyps, and is associated with anemia, right-colon polyps, and adenomas. The risk of polyps and of colorectal cancer in relatives of persons with JPC requires further study.

Celiac autoimmunity in children with type 1 diabetes: a two-year follow-up.

OBJECTIVE To determine the benefits of screening for celiac autoimmunity via immunoglobulin A transglutaminase autoantibodies (TG) in children with type 1 diabetes (T1D). STUDY DESIGN We followed up 79 screening-identified TG+ and 56 matched TG- children with T1D for 2 years to evaluate growth, bone mineral density, nutritional status, and diabetes control. TG+ subjects self-selected to gluten-free or gluten-containing diet. RESULTS Of the initial cohort, 80% were available for reexamination after 2 years. TG+ subjects had consistently lower weight z-scores and higher urine N-telopeptides than TG- subjects, but similar measures of bone density and diabetes outcomes. TG+ children who remained on a gluten-containing diet had lower insulin-like growth factor binding protein 3 z-scores compared with TG+ subjects who reported following a gluten-free diet. Children who continued with high TG index throughout the study had lower bone mineral density z-scores, ferritin, and vitamin D 25OH levels, compared with the TG- group. CONCLUSIONS No significant adverse outcomes were identified in children with T1D with screening-identified TG+ who delay therapy with a gluten-free diet for 2 years. Children with persistently high levels of TG may be at greater risk. The optimal timing of screening and treatment for celiac disease in children with T1D requires further investigation.