Anemia in Children With Inflammatory Bowel Disease: A Position Paper by the IBD Committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition.

Anemia is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). It can be asymptomatic or associated with nonspecific symptoms, such as irritability, headaches, fatigue, dizziness, and anorexia. In IBD patients, the etiology of anemia is often multifactorial. Various causes include iron deficiency, anemia of inflammation and chronic disease, vitamin deficiencies, hemolysis, or myelosuppressive effect of drugs. Anemia and iron deficiency in these patients may be underestimated because of their insidious onset, lack of standardized screening practices, and possibly underappreciation that treatment of anemia is also required when treating IBD. Practitioners may hesitate to use oral preparations because of their intolerance whereas intravenous preparations are underutilized because of fear of adverse events, availability, and cost. Several publications in recent years have documented the safety and comparative efficacy of various intravenous preparations. This article reviews management of anemia in children with IBD, including diagnosis, etiopathogenesis, evaluation of a patient, protocol to screen and monitor patients for early detection and response to therapy, treatment including parenteral iron therapy, and newer approaches in management of anemia of chronic disease. This report has been compiled by a group of pediatric gastroenterologists serving on the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) IBD committee, in collaboration with a pediatric hematologist, pharmacist, and a registered dietician who specializes in pediatric IBD (IBD Anemia Working Group), after an extensive review of the current literature. The purpose of this review is to raise awareness of under-diagnosis of anemia in children with IBD and make recommendations for screening, testing, and treatment in this population.

Difference in Pathomechanism Between Crohn's Disease and Ulcerative Colitis Revealed by Colon Transcriptome.

BACKGROUND: We aim to identify the differences in colonic mucosal transcriptome between Crohn's disease (CD) and ulcerative colitis (UC) for a better understanding of the molecular pathology. METHODS: Differentially expressed genes (DEG) in the colonic mucosa of CD and UC were identified with a global gene expression microarray dataset generated from the colon biopsies of CD and UC patients and normal controls. The DEGs were then processed to identify altered pathways and modularized DEGs and pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis with an independent cohort of samples was performed to validate the microarray data. RESULTS: At the pathway level, virus infection and autoimmune pathways were upregulated in CD but not in UC when compared with controls. Some of the relevant DEGs (such as TAP1 and TAP2) were elevated in both CD and UC, with CD exhibiting more pronounced elevations. Gene expression levels in viral infection pathways were correlated with those of autoimmune pathways. In contrast, pattern recognition-mediated innate immune pathways (TLR4 and TLR2) were significantly elevated in UC but not in CD. Similar results were observed with an independent cohort by qRT-PCR. CONCLUSIONS: Our data support the hypothesis that viral infection induced autoimmunity may represent a pathomechanism for IBD, especially CD. However, pattern recognition-mediated innate immunity targeting microbiome may play a more important role in UC compared with CD. Our findings identified different intervention targets for CD and UC, which may lead to more effective treatments for IBD patients.

Anemia in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Anemia is the most frequent extra-intestinal finding in inflammatory bowel disease (IBD). The aim of this study is to determine the prevalence and types of anemia in pediatric patients with IBD at diagnosis and at approximately 1 year follow-up. METHODS: This is a retrospective chart review of patients diagnosed with IBD from 2005 to 2012, ages 1 to 18 years. Patients who had hemoglobin, hematocrit, mean corpuscular volume, and iron indices obtained at the time of diagnosis and at approximately 1 year follow-up were included in the study. The prevalence of anemia at the beginning and the end of the study was recorded. Using the soluble transferrin receptor index the type of anemia was determined. RESULTS: At diagnosis, 67.31% of patients were anemic. Overall, 28.85% of patients had either iron deficiency anemia (IDA) or a combination of IDA and anemia of chronic disease (ACD), whereas 38.46% had ACD alone. At follow-up, 20.51% were anemic. 15.38% had either IDA or a combination of IDA and ACD; 5.13% had ACD alone. The pattern of anemia and response to therapy differed among the IBD phenotypes CONCLUSIONS:: Anemia is frequent in inflammatory bowel disease. The prevalence was higher in Crohn disease (CD). At 1 year, the prevalence of anemia decreased significantly, but persisted. Anemia of chronic disease predominated in CD. Iron deficiency anemia continued to be present in CD and ulcerative colitis.

Poor Agreement Between Imaging and Histologic and Colonoscopy Findings in Pediatric Patients.

BACKGROUND: Computed tomography scans (CTs), more recently magnetic resonance imaging, are often used to assess the gastrointestinal tract in patients complaining of abdominal pain. We aim to determine the strength of agreement among abdominal imaging, endoscopic, and histologic findings. METHODS: Retrospective chart review of pediatric patients who underwent colonoscopy between January 1, 2012, and December 31, 2014, at Women and Children's Hospital of Buffalo. Patients who had abdominal and pelvic CTs or magnetic resonance imaging within 30 days before or after a colonoscopy were included. RESULTS: One hundred two patients were included: mean age 12.7 ±â€Š3.8 years, 66% girls. A total of 109 imaging studies were performed. Overall 61% of imaging studies were abnormal. The most frequent intestinal radiological findings were colonic wall thickening (CWT) (55%) and colonic wall enhancement (CWH) (24%). Free fluid (20%) and fat stranding (18%) were the most common extra-intestinal findings. Imaging studies agreed with histology in 81% and with colonoscopy in 75% with a moderate strength of agreement (k: 0.59 and 0.466, respectively). CWT agreed with histology in 74% with a moderate strength of agreement (k: 0.47). History of weight loss (OR 5.35, P = 0.041), chronic diarrhea (OR 4.22, P = 0.014), a positive lactoferrin (OR 7.00, P = 0.011), and presence of CWT on imaging study (OR 5.20, P = 0.001) were predictive of having abnormal histology. CONCLUSIONS: The strength of agreement among imaging, endoscopic, and histologic findings was suboptimal. Colonoscopy and imaging are both likely to be necessary in patients with suspected inflammatory bowel disease. Although colonoscopy may be superior in diagnosis of colitis, imaging may provide more information regarding small bowel disease.

Outcome of medical management of intraabdominal abscesses in children with Crohn disease.

INTRODUCTION: Crohn disease (CD) is a chronic inflammatory condition of the gastrointestinal tract that is complicated by fistulas, strictures, and intraabdominal abscesses (IAA) in 10%-30% of patients. To avoid surgical resection of the bowel, medical therapy with antibiotics (Ab) with or without percutaneous drainage (PD) is first undertaken. Our objectives are to examine the outcome of IAA in CD patients treated with antibiotics alone vs antibiotics and PD, and to identify risk factors for medical therapy failure. METHODS: Charts for patient with CD who were diagnosed between 2004 and 2016 at the Women and Children's Hospital of Buffalo were retrospectively reviewed. We compared the two modalities of medical therapy (Ab + PD vs Ab alone) in terms of abscess resolution and the need for surgical intervention. RESULTS: Twenty-nine patients, ages ranging from 12 to 18years, mean 15.5±2.5, 48% Male with IAA were identified. Overall, 69% of abscesses failed medical therapy including 87% of the drained abscesses and 50% of nondrained abscesses, p=0.04. The abscesses that failed medical therapy were more likely to have been drained (P=0.03) as they were larger in size (P = 0.03), patients were more likely to have a known CD on immunosuppression (P=0.016), and more likely to have an associated upper GI disease (P=0.002), when compared to those that were successful with medical therapy alone. CONCLUSION: Our results show that the majority of our patients required surgical intervention for abscess treatment and resolution of associated findings despite drainage. Risk factors include big drainable abscesses, developing IAA while on immunosuppression, and a more extensive disease with associated fistulae and strictures. Small undrainable abscesses are likely to resolve with antibiotics alone, therefore early detection and treatment are essential. TYPE OF STUDY: Level 2, retrospective study.

Structural changes in the gut microbiome of constipated patients.

Previous studies using culture-based methods suggested an association between constipation and altered abundance of certain taxa of the colonic microbiome. We aim to examine the global changes in gut microbial composition of constipated patients. A cross-sectional pilot study using 16S rRNA gene pyrosequencing was performed to compare stool microbial composition of eight constipated patients and 14 nonconstipated controls. Only obese children were enrolled so that the microbiome features associated with constipation would not be obscured by those associated with obesity. The sequencing reads were processed by QIIME for quantitative analysis of the microbial composition at genus and above levels. Dietary intake for all the individuals was assessed by dietary recalls and a food frequency questionnaire. The ecological diversities of fecal microbiome of the constipated patients differed from those of the controls. Significantly decreased abundance in Prevotella and increased representation in several genera of Firmicutes were observed in constipated patients compared with controls. The conventional probiotic genera Lactobacillus and Bifidobacteria were not decreased in the microbiomes of the constipated patients. These alterations in the fecal microbiome of constipated patients suggested that a novel probiotic treatment including certain Prevotella strains may be more effective than conventional probiotic products incorporating Lactobacillus or Bifidobacterium species. While it is possible that the observed changes in the microbiome in constipated subjects are a consequence of a low-fiber diet, these changes also predict a different pattern of bacterial fermentation end-products, such as increased butyrate production, which may contribute to pathogenesis of constipation.

Vitamin and zinc status pretreatment and posttreatment in patients with inflammatory bowel disease.

Vitamin deficiencies are common in inflammatory bowel disease. Here we present 5-year follow-up data of 61 patients. No folate or vitamin B12 deficiency was identified throughout the study. A daily multivitamin supplement was sufficient to replete 100% of vitamin A-deficient and vitamin E-deficient patients. A total of 52% of vitamin D-deficient patients corrected, but 15% who had normal vitamin D levels at diagnosis developed deficiency. A total of 63% of zinc-deficient patients normalized their zinc status, but 15% developed zinc deficiency at follow-up despite supplementation.

Endotoxemia unrequired in the pathogenesis of pediatric nonalcoholic steatohepatitis.

BACKGROUND AND AIM: Nonalcoholic steatohepatitis (NASH), the severe form of nonalcoholic fatty liver disease, is a serious liver complication associated with obesity. Several studies suggest that endotoxemia is associated with nonalcoholic fatty liver disease and NASH. We aimed to study the correlation of gut microbiome composition and the incidence of endotoxemia in obese patients and NASH patients in comparison with normal controls. METHODS: The abundance of Gram-negative bacteria in the gut microbiomes of normal controls, obese patients with normal liver, and biopsy-proven NASH patients were assessed using 16S rRNA pyrosequencing data. Serum endotoxin was determined by endpoint limulus amebocyte lysate assay. RESULTS: Higher abundance of Gram-negative bacteria in gut microbiome was observed in obese and NASH patients in comparison with normal controls, but no difference was detected between obese and NASH patients. Serum endotoxin is higher in the NASH group than the normal controls. In addition, the obese and NASH patients had a higher incidence of endotoxemia compared with normal controls. However, Spearman's test found no correlation between the abundance of Gram-negative bacteria and serum endotoxin levels. The majority of the NASH patients and the obese patients had low serum endotoxin level. Among NASH patients, serum endotoxin is not correlated with disease severity. CONCLUSIONS: Our data suggest that the gut microbiome composition does not contribute to the incidence of endotoxemia in NASH, and endotoxemia is not required in the pathogenesis of NASH. Our observations highlight the current concept that multiple factors contribute to the development of NASH.

Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH.

UNLABELLED: Nonalcoholic steatohepatitis (NASH) is a serious liver disease associated with obesity. Characterized by metabolic syndrome, hepatic steatosis, and liver inflammation, NASH is believed to be under the influence of the gut microflora. Here, the composition of gut bacterial communities of NASH, obese, and healthy children was determined by 16S ribosomal RNA pyrosequencing. In addition, peripheral blood ethanol was analyzed to monitor endogenous ethanol production of patients and healthy controls. UniFrac-based principle coordinates analysis indicated that most of the microbiome samples clustered by disease status. Each group was associated with a unique pattern of enterotypes. Differences were abundant at phylum, family, and genus levels between healthy subjects and obese patients (with or without NASH), and relatively fewer differences were observed between obese and the NASH microbiomes. Among those taxa with greater than 1% representation in any of the disease groups, Proteobacteria, Enterobacteriaceae, and Escherichia were the only phylum, family and genus types exhibiting significant difference between obese and NASH microbiomes. Similar blood-ethanol concentrations were observed between healthy subjects and obese non-NASH patients, but NASH patients exhibited significantly elevated blood ethanol levels. CONCLUSIONS: The increased abundance of alcohol-producing bacteria in NASH microbiomes, elevated blood-ethanol concentration in NASH patients, and the well-established role of alcohol metabolism in oxidative stress and, consequently, liver inflammation suggest a role for alcohol-producing microbiota in the pathogenesis of NASH. We postulate that the distinct composition of the gut microbiome among NASH, obese, and healthy controls could offer a target for intervention or a marker for disease.

Vitamin and mineral status in patients with inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) are at risk for vitamin and mineral deficiencies because of long-term inflammation in the gut mucosa and decreased oral intake. The aim of the study is to investigate the prevalence of vitamin and zinc deficiencies in patients with newly diagnosed IBD compared with a control group. METHODS: This is a retrospective chart review of all of the patients diagnosed as having IBD from 2006 to 2010, ages 1 to 18 years. Patients who had fat- and water-soluble vitamins (A, E, D 25-OH, folate, and B(12)) and zinc levels obtained at time of diagnosis were included in the study. A total of 61 patients with IBD and 61 age- and sex-matched controls were included. RESULTS: None of the 61 patients with IBD had folate or vitamin B12 deficiency. Vitamin D deficiency was found in 62% of the patients, vitamin A deficiency in 16%, vitamin E deficiency in 5%, and zinc deficiency in 40%. The control group had vitamin D and E and zinc deficiency in 75%, 8%, and 19% patients, respectively. CONCLUSIONS: We conclude that vitamin B12 and folate deficiencies are rare in children with newly diagnosed IBD in the United States and we question whether routine monitoring is warranted. Vitamin A and zinc deficiency are common in patients with newly diagnosed IBD and levels should be assessed at the time of diagnosis so that enteral repletion can commence. Vitamin D deficiency is common in all of the children in the Buffalo, NY, area, and routine screening for this deficiency is warranted.

Effect of dietary advanced glycation end products on mouse liver.

UNLABELLED: The exact pathophysiology of non-alcoholic steatohepatitis (NASH) is not known. Previous studies suggest that dietary advanced glycation end products (AGEs) can cause oxidative stress in liver. We aim to study the effects of dietary AGEs on liver health and their possible role in the pathogenesis of NASH. METHODS: Two groups of mice were fed the same diet except the AGE content varied. One group was fed a high AGE diet and the second group was fed a regular AGE diet. Liver histology, alanine aminotransferase, aspartate aminotransferase, fasting glucose, fasting insulin, insulin resistance and glucose tolerance were assessed. RESULTS: Histology revealed that neutrophil infiltration occurred in the livers of the high AGE group at week 26; steatosis did not accompany liver inflammation. At week 39 livers from both groups exhibited macro- or micro-steatosis, yet no inflammation was detected. Higher insulin levels were detected in the regular AGE group at week 26 (P = 0.034), compared to the high AGE group. At week 39, the regular AGE group showed higher levels of alanine aminotransferase (P<0.01) and aspartate aminotransferase (P = 0.02) than those of the high AGE group. CONCLUSIONS: We demonstrate that a high AGE diet can cause liver inflammation in the absence of steatosis. Our results show that dietary AGEs could play a role in initiating liver inflammation contributing to the disease progression of NASH. Our observation that the inflammation caused by high AGE alone did not persist suggests interesting future directions to investigate how AGEs contribute to pro-oxidative and anti-oxidative pathways in the liver.

Esophagitis in children with celiac disease.

Objectives. To our knowledge, the occurrence of esophagitis in children with celiac disease (CD) has never been evaluated. The aim of this study is to determine the prevalence of esophagitis in children with CD. Patients and Methods. Between 2003 and 2007, children with biopsy confirmed CD were retrospectively identified. Biopsy reports were reviewed for esophageal inflammation. Biopsy reports of 2218 endoscopies performed during the same period were also evaluated for inflammation. Results. Forty-nine children diagnosed with CD (47% boys). Nineteen of 49 (39%) patients with CD had esophagitis (95% CI 0.23-0.5). Thirty percent of boys and 46% of girls with CD had esophagitis (95% CI 0.12-0.40). Overall, 45% of patients who underwent upper endoscopy had esophagitis. The prevalence of esophagitis in CD (39%) compared to the prevalence of esophagitis (45%) in our practice was not significantly different, P = 0.2526. Conclusion. There was no difference in the prevalence of esophagitis between children diagnosed with CD at the time of their diagnostic EGD and the prevalence of esophagitis in children without CD. A prospective study to determine whether the esophagitis should be treated with acid suppression or whether the esophagitis heals with the gluten-free diet is warranted.