Chronic Inflammation Permanently Reshapes Tissue-Resident Immunity in Celiac Disease.

Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD. VIDEO ABSTRACT.

Factors Affecting Selenium Status in Infants on Parenteral Nutrition Therapy.

INTRODUCTION: Selenium is an essential micronutrient that must be supplemented in infants and young children on exclusive parenteral nutrition (PN). We examined selenium status and clinical factors associated with a deficiency in infants on PN. METHODS: This was a retrospective cohort study of pediatric patients receiving PN with routine monitoring of selenium status. Deficiency was diagnosed using age-based norms of plasma selenium status. Associations between selenium deficiency and the following clinical factors were examined: birthweight status: extremely low birthweight (ELBW) versus very low birthweight (VLBW) versus low birthweight (LBW) versus normal birthweight (NBW), serum albumin status, presence of cholestasis, and co-administration of enteral feeds. RESULTS: A total of 42 infants were included with gestational age [median (interquartile range)] 28 weeks (25,34). The prevalence of selenium deficiency was 80% and the prevalence of albumin deficiency was 87.5%. The odds of selenium deficiency were higher in ELBW infants (odds ratio = 17.84, 95% confidence interval [4.04-78.72], P < 0.001) and VLBW infants (odds ratio = 16.26, 95% confidence interval [1.96-135.04], P < 0.001) compared to NBW infants. The odds of selenium deficiency were 5-fold higher in patients with low serum albumin (odds ratio = 5.33, 95% confidence interval [1.39-20.42], P = 0.015). There were no associations seen between selenium status and presence of cholestasis or co-administration of enteral feeds. CONCLUSION: In this cohort of infants on PN therapy, the main clinical factors associated with selenium deficiency were presence of hypoalbuminemia and history of ELBW or VLBW. These findings support dual measurement of serum albumin and serum selenium to improve interpretation of selenium status.

A Narrow Window: Booming Gluten-free Market and Fostering Healthy Dietary Habits in Children With Celiac Disease.

An expanding gluten-free marketplace has left children with celiac disease and their families with a host of new dietary options. The quality of these foods is inconsistent and processed items may be high in caloric content while lacking nutritional value. Assessing the dietary preferences of a cohort of children with celiac disease via cross-sectional survey, we find that these processed food items have become a staple of the gluten-free diet, and in many cases, these foods are consumed to the exclusion of healthy alternatives. Furthermore, children with celiac disease and their families become less interested in dietary education over time, indicating that the greatest opportunity for imparting a healthy diet may occur at the time of diagnosis.

Effects of the Gluten-free Diet on Body Mass Indexes in Pediatric Celiac Patients.

OBJECTIVE: The aim of the study was to determine the effects of the gluten-free diet (GFD) on body mass indexes (BMIs) in children with celiac disease at University of Chicago before and after 2011, when processed gluten-free foods became readily available on the market. METHODS: We conducted a retrospective chart review of children seen at University of Chicago Celiac Center from January 2002 to May 2016. BMI was recorded upon GFD initiation in addition to at least 1 other timepoint: 6 months, 1 year, 2 years, 3 years, and 4+ years. We compared the rate of BMI increase in children who were diagnosed before versus after 2011. RESULTS: A total of 147 children (66% girls) with biopsy-confirmed celiac disease were included in the study. The mean BMI at diagnosis was 17.8 (standard deviation 3.9) for those diagnosed before 2011 and 17.1 (standard deviation 2.7) for those diagnosed after 2011. Based on a mixed-effects random-intercept random-slope regression model, there was no evidence for significant difference in BMI change over time between the 2 groups (P value = 0.36). BMI values overall were noted to increase after starting the GFD, even at the first appointment. Serologies were monitored after patients started the GFD and approached normal values, allowing us to conclude that patients were adherent to the GFD. CONCLUSIONS: Although overall we observed no significant changes in BMI before and after 2011, we did notice that in adolescent celiac patients there was a trend toward a higher postdiagnosis BMI in the years after 2011. We speculate that teenagers may be especially vulnerable to choosing quick and easy processed gluten-free options over more healthy, natural alternatives leading to a rise in their BMIs after the 2011 surge in production of processed gluten-free foods on the market. Therefore, special attention must be paid to this population to insure ongoing healthy food choices even after many years on the GFD.

Celiac Disease Symptom Resolution: Effectiveness of the Gluten-free Diet.

OBJECTIVE: The aim of the study was to evaluate the efficacy of the gluten-free diet (GFD) on gastrointestinal (GI) and extra-intestinal (EI) symptom resolution and identify predictors for persistence of symptoms in all celiac patients at the University of Chicago. METHODS: We conducted a retrospective chart review from 2002 to 2015. GI symptoms included abdominal pain, bloating, constipation, diarrhea, failure to thrive/weight loss, nausea, reflux, and vomiting. EI symptoms included abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgia, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility. RESULTS: A total of 554 patients (227 children) with celiac disease (CeD) were included. Abdominal pain, diarrhea and failure to thrive were the most common GI symptoms in children whereas diarrhea, bloating, and abdominal pain were most common in adults. Short stature, fatigue, and headache were the most common EI symptoms in children whereas iron deficiency anemia, fatigue, and headache/psychiatric disorders were most common in adults. Children had significantly higher rates of EI and GI symptom resolution as compared to adults, with greater rates of improvements in GI versus EI symptoms at more than 24 months. Long duration of symptoms, female sex, and non-adherence to a GFD were the most important significant predictors of failure to clinically improve. CONCLUSIONS: 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 over EI symptoms. Early recognition of CeD and close attention to diet adherence may help in symptom resolution.

Celiac Disease and Wheat Intolerance Syndrome: A Critical Update and Reappraisal.

Since the first description of celiac disease (CeD) by Samuel Gee in 1888 and the later "miraculous discovery" that bread was responsible for this condition following World War II in Europe, there has been an exponential growth of knowledge regarding CeD. Just when we thought that we knew everything there was to know about it, the disease is, however, offering new challenges, with its presentation having significantly morphed over the years from cases of overt gastrointestinal symptoms, malnutrition, and atrophic villi on duodenal biopsies to that of largely extraintestinal, subtle, or mild symptoms. Along with these changes, unexpectedly a new parallel entity appeared a few years ago and is gaining ground: the so-called nonceliac gluten sensitivity, an improper name because it should actually be referred to as wheat intolerance syndrome given that the role of gluten in all such cases is far from demonstrated and the implication of an immune involvement suggested by the term "sensitivity" is still unfounded. Lastly, wheat can be an offender also through an immunoglobulin E-mediated allergy, whose presence must also be evaluated and ruled out in selected cases.The practicing physician is therefore now challenged with the task of discerning which patients need to be assessed for one or the other of these disorders, and how.This review aims at providing an updated, critical reassessment of these 2 entities.

Extraintestinal Manifestations of Celiac Disease: Effectiveness of the Gluten-Free Diet.

OBJECTIVE: The aim of the study was to evaluate the effectiveness of the gluten-free diet (GFD) on extraintestinal symptoms in pediatric and adult celiac populations at the University of Chicago. METHODS: We conducted a retrospective chart review of the University of Chicago Celiac Center clinic charts from January 2002 to October 2014. Demographics, serologic testing, intestinal biopsies, and extraintestinal symptoms at presentation, 12, 24, and >24 months were recorded. Extraintestinal symptoms included abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgias, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility. RESULTS: A total of 737 patients with biopsy-confirmed celiac disease or skin biopsy-confirmed dermatitis herpetiformis were included. Patients lost to follow-up, or with insufficient data were excluded leaving 328 patients (157 pediatrics younger than 18 years). For pediatrics, the female to male ratio was 2:1 and the mean age at diagnosis was 8.9 years. For adults, 4:1 and 40.6 years old. Extraintestinal symptom rates were similar in children (60%) and adults (62%). Short stature (33%), fatigue (28%), and headache (20%) were most common in children. Iron deficiency anemia (48%), fatigue (37%), and headache/psychiatric disorders (24%) were common in adults. Children had faster/higher rates of symptom resolution compared with adults. Twenty-eight percent of children with unresolved short stature on a GFD were found to have other comorbidities. CONCLUSIONS: Children and adults with celiac disease have similar rates of extraintestinal manifestations. In children short stature, fatigue, and headache were most common, whereas anemia, fatigue, and headache/psychiatric disorders were most common in adults. Children on a strict GFD showed faster and higher rates of symptom resolution as compared to adults. Unresponsive children with short stature must be assessed for comorbidities.

Bile acid pool dynamics in progressive familial intrahepatic cholestasis with partial external bile diversion.

OBJECTIVES: Partial external bile diversion (PEBD) is an established therapy for low-γ-glutamyl transferase (GGT) progressive familial intrahepatic cholestasis (PFIC). This study sought to determine whether the dynamics of the cholic acid (CA) and chenodeoxycholic acid (CDCA) pools in subjects with low-GGT-PFIC with successful PEBD were equivalent to those achieved with successful liver transplantation (LTX). METHODS: The kinetics of CA and CDCA metabolism were measured by stable isotope dilution in plasma samples in 5 subjects with PEBD, all with intact canalicular bile salt export pump expression and compared with subjects with low-GGT-PFIC with successful LTX. Stomal loss of bile acids was measured in subjects with PEBD. RESULTS: The fractional turnover rate for CA in the PEBD group ranged from 0.5 to 4.2/day (LTX group, range 0.2-0.9/day, P = 0.076) and for CDCA from 0.7 to 4.5/day (LTX group 0.3-0.4/day, P = 0.009). The CA and CDCA pool sizes were equivalent between groups; however, pool composition in PEBD was somewhat more hydrophilic. The CA/CDCA ratio in PEBD ranged from 0.9 to 19.5, whereas in LTX it ranged from 0.5 to 2.6. Synthesis rates computed from isotope dilution correlated well with timed output for both CA (r2 = 0.760, P = 0.024) and CDCA (r2 = 0.690, P = 0.021). CONCLUSIONS: PEBD results in bile acid fractional turnover rates greater than LTX, pool sizes equivalent to LTX, and pool composition that is at least as hydrophilic as produced by LTX.

Nausea predicts delayed gastric emptying in children.

OBJECTIVES: To assess whether the gastroparesis cardinal symptom index (GCSI), or any individual symptom, is associated with delayed gastric emptying in children, and to assess understanding of symptoms associated with delayed gastric emptying. STUDY DESIGN: Fifty children (36 F), 5-18 years of age, undergoing gastric emptying scintigraphy (GES) at Lurie Children's Hospital in Chicago, Illinois, completed Likert-type GCSI and symptom comprehension questionnaires. Correlation of GES results (normal or abnormal) with questionnaire results using the Wilcoxon rank sum test. RESULTS: Seventy percent of subjects had a normal GES. Children reported understanding most terms of GCSI (average score 2.59, range 0-3). The GCSI was not associated with delayed gastric emptying. Nausea was associated with delayed gastric emptying only (numerical P = .04, word P = .02). Results were not altered when poorly understood terms were excluded. CONCLUSIONS: The GCSI is not associated with delayed gastric emptying in children. Lack of association does not seem to be related to lack of understanding. Nausea alone was the only symptom that showed an association with delayed gastric emptying on GES.

Not Quite Meeting the Mark: College Experiences for Patients With Celiac Disease.

Strict adherence to a gluten-free diet (GFD), the current treatment for celiac disease (CD), is socially challenging for adolescents, especially in the college setting. We conducted a survey of factors contributing to GFD adherence during college among patients meeting the ESPGHAN criteria for CD. One-hundred-one young adults (18 years and older) were contacted; 59 completed the survey, of which 47 were enrolled or had attended college. The survey was developed by the study team. Most patients were able to maintain strict adherence to the GFD, whereas at college and reported that GF food was available and consistent with expectations. Nearly all participants reported a lack of resources for students with CD. Strong family support helped, and school stress and lack of peer support impeded diet adherence. Although colleges may meet the basic needs of celiac students, the availability and quality of gluten-free options, and improved campus resources are needed.

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in µm), crypt depth (CrD, in µm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

Call for Action: High Rates of Depression in the Pediatric Celiac Disease Population Impacts Quality of Life.

To test the impact of celiac disease (CD) and depression symptoms on quality of life in adolescent patients. Methods: We conducted a prospective survey of 12- to 18-year-old celiac patients and their caregivers between January 2015 and November 2016. Enrolled parents and youth completed standard measures of adjustment to celiac disease, depression, and quality of life. Results: We enrolled 105 patients with CD and their parents. Both parents and youth reported high levels of depression symptoms. There were no associations between age, duration of CD, or following a gluten-free diet (GFD) and quality of life. No significant associations were found between adolescent perception of CD state and quality of life; parental report of adolescent's adjustment to CD; and youth report of quality of life were modestly associated (r = 0.19, P ≤ 0.05). Moderate associations were observed between adolescent reports of depression and quality of life (r = 0.59, P < 0.01) and between parental reports of adolescent depression and quality of life (r = 0.41, P = 0.01). Only depressive symptoms by youth and parent report, however, and not adjustment to celiac, explained unique variance in quality of life. Conclusion: Adolescents with CD report levels of depression comparable to those reported by adolescents seeking mental health services. Length of time living with CD, or on GFD, age at diagnosis and perception of disease state do not appear to contribute to depression. High rates of depression may impact CD prognosis, therefore, screening for depression in adolescents with CD appears critical. Identification and intervention of depression may lead to improved adherence to the GFD during emerging adulthood.

The Gluten Free Diet's Impact on Growth in Children with Celiac Disease in Two Different Countries.

The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric patients with celiac disease (CD) and their dependence on different socio-cultural environments are poorly known. We conducted an international retrospective study on celiac patients diagnosed at the University of Verona, Italy, and at the University of Chicago, Chicago, IL, USA, as underweight. A total of 140 celiac children and 140 controls (mean age 8.4 years) were enrolled in Chicago; 125 celiac children and 125 controls (mean age 7.3 years, NS) in Verona. At time of diagnosis, Italian celiac children had a weight slightly lower (p = 0.060) and a BMI z-score significantly (p < 0.001) lower than their American counterparts. On GFD, Italian celiac children showed an increased prevalence of both underweight (19%) as well as overweight (9%), while American children showed a decrease prevalence of overweight/obese. We concluded that while the GFD had a similar impact on growth of celiac children in both countries, the BMI z-score rose more in American than in Italian celiac children. Additionally, in Italy, there was an alarming increase in the proportion of celiac children becoming underweight. We speculate that lifestyle and cultural differences may explain the observed variations.

Extra-Intestinal Manifestation of Celiac Disease in Children.

The aim of this literature review is to discuss the extra-intestinal manifestations of celiac disease within the pediatric celiac population.

An Overview of Cirrhosis in Children.

Cirrhosis is the end result of nearly all forms of progressive liver disease. The diffuse hepatic process can be characterized as a state of inflammation progressing to fibrosis and resulting in nodular regeneration, ultimately leading to disorganized liver architecture and function. The underlying etiology of cirrhosis in children may often differ from adults owing to specific disease processes that manifest in childhood, including biliary atresia, galactosemia, and neonatal hepatitis. Although basic management strategies in children are similar to those in adults, the care given to children with cirrhosis must keep the child's growth and development of paramount importance. [Pediatr Ann. 2016;45(12):e427-e432.].