Ernest G. Seidman

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.

Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease

BACKGROUND & AIMS The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype. METHODS Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype. RESULTS Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy. CONCLUSIONS 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.

Direct and Indirect Induction by 1,25-Dihydroxyvitamin D3 of the NOD2/CARD15-Defensin β2 Innate Immune Pathway Defective in Crohn Disease

Vitamin D signaling through its nuclear vitamin D receptor has emerged as a key regulator of innate immunity in humans. Here we show that hormonal vitamin D, 1,25-dihydroxyvitamin D3, robustly stimulates expression of pattern recognition receptor NOD2/CARD15/IBD1 gene and protein in primary human monocytic and epithelial cells. The vitamin D receptor signals through distal enhancers in the NOD2 gene, whose function was validated by chromatin immunoprecipitation and chromatin conformation capture assays. A key downstream signaling consequence of NOD2 activation by agonist muramyl dipeptide is stimulation of NF-κB transcription factor function, which induces expression of the gene encoding antimicrobial peptide defensin β2 (DEFB2/HBD2). Pretreatment with 1,25-dihydroxyvitamin D3 synergistically induced NF-κB function and expression of genes encoding DEFB2/HBD2 and antimicrobial peptide cathelicidin in the presence of muramyl dipeptide. Importantly, this synergistic response was also seen in macrophages from a donor wild type for NOD2 but was absent in macrophages from patients with Crohn disease homozygous for non-functional NOD2 variants. These studies provide strong molecular links between vitamin D deficiency and the genetics of Crohn disease, a chronic incurable inflammatory bowel condition, as Crohns pathogenesis is associated with attenuated NOD2 or DEFB2/HBD2 function.

Chronic intermittent elemental diet improves growth failure in children with Crohn's disease

Growth failure often complicates Crohns disease in pediatric patients and is principally due to inadequate caloric intake. To assess whether intermittent courses of an elemental diet could reestablish growth, 8 children (aged 9.8-14.2 yr) with Crohns disease and growth failure entered into a prospective trial. Each patient was studied during an observation year on standard therapy, then for an experimental year during which they received enteral elemental diet 1 out of 4 mo. An age- and disease-matched control group of 4 patients was treated by conventional medical therapy during both years. Elemental diet therapy was administered nocturnally, at home, by continuous nasogastric infusion and increased the daily caloric intake by 25% (p less than 0.01). Anthropometric measurements demonstrated significant height and weight gains in the elemental diet group vs. controls (p less than 0.01). Crohns disease activity index and prednisone intake decreased significantly in patients receiving elemental diet therapy when compared with themselves and with controls on conventional medical therapy (p less than 0.05). In contrast, the rate of pubertal development was similar in both groups irrespective of the treatment modality. This study demonstrates that chronic intermittent elemental diet effectively reverses growth arrest, while decreasing prednisone requirements and Crohns disease activity index in pediatric Crohns disease patients prior to puberty.

Caco-2 cells as a model for intestinal lipoprotein synthesis and secretion.

Caco‐2 cells, an intestinal cell line derived from a human colorectal carcinoma that spontaneously differentiates under standard culture conditions, lends itself to the in vitro study of human gut in view of its efficient intestinal transport processes. Among its multiple biological functions are those related to the absorption, transport, and metabolism of lipids and lipoproteins. Despite their intestinal origin, confluent Caco‐2 cell monolayers primarily express L‐FABP for the uptake of apical dietary long chain fatty acids, incorporating them into triglycerides by the glycerol 3‐phosphate pathway, and assembling very‐low‐density lipoprotein, high‐density lipoprotein, and low‐density lipoprotein. The monoacylglycerol pathway is inactive in Caco‐2 cells. Furthermore, the secretion of newly synthesized triglyceride‐rich lipoproteins is very restricted, despite abundant production of apolipoprotein (apo) B. The regulation of apoB synthesis and its mRNA editing at the enterocyte level has been intensively examined in Caco‐2 cells. Luminal fatty acids, calcium ion, as well as vitamins and hormones are known to modulate the apoB‐48/apoB‐100 at the transcriptional and/or translational level. The regulation of 3‐hydroxy‐3‐methylglutaryl‐CoA reductase and acyl‐CoA: (cholesterol acyltransferase), the key enzymes governing intracellular cholesterol handling, have also been extensively examined in Caco‐2 cells. In many respects this cell line provides an excellent in vitro model for the investigation of intestinal lipoprotein metabolism; however, their limited secretion capacity remains a potential drawback to comparisons with the in vivo physiological state.—Levy, E., Mehran, M., Seidman, E. Caco‐2 cells as a model for intestinal lipoprotein synthesis and secretion. FASEB J. 9, 626‐635 (1995)

Imbalances in Dietary Consumption of Fatty Acids, Vegetables, and Fruits Are Associated With Risk for Crohn's Disease in Children

BACKGROUND AND OBJECTIVES:The role of dietary factors in the etiology of Crohns disease (CD) is inconsistent largely due to difficulties in acquiring valid information on consumption habits. We examined the impact of diet on new onset CD in children using a validated food-frequency questionnaire (FFQ).METHODOLOGY:A case-control study was carried out. Children ≤20 yr, newly diagnosed with CD, were recruited from 3 pediatric gastroenterology clinics across Canada. Population or hospital controls were selected matched to cases for time of diagnosis (±6 months) and area of residence. Dietary consumption 1 yr prior to disease diagnosis was evaluated using a validated FFQ, administered within 1 month of diagnosis. Conditional logistic regression analysis adjusting for potential confounding variables (energy intake, age, gender, body mass index) was carried out.RESULTS: A total of 130 CD patients and 202 controls were studied. Mean age at diagnosis (±SD) was 14.2 (2.7). There were more male patients (59%). Comparing the highest to the lowest levels of consumption, higher amounts of vegetables (OR 0.69, 95% CI 0.33–1.44, P = 0.03), fruits (OR 0.49, 95% CI 0.25–0.96, P = 0.02), fish (OR 0.46, 95% CI 0.20–1.06, P = 0.02), and dietary fiber (OR 0.12, 95% CI 0.04–0.37, P < 0.001) protected from CD. Consumption of long-chain omega-3 fatty acids (LCN-ω-3) was negatively associated with CD (OR 0.44, 95% CI 0.19–1.00, P < 0.001). A higher ratio of LCN-ω-3/ω-6 fatty acids was significantly associated with lower risks for CD (OR 0.32, 95% CI 0.14–0.71, P = 0.02).CONCLUSIONS: Our findings indicate that an imbalance in consumption of fatty acids, vegetables, and fruits is associated with increased risks for CD among Canadian children.

Pathogenesis of Shiga toxin-associated hemolytic uremic syndrome

The aim of this review is to examine recent advances in experimental and clinical research relevant to the pathogenesis of diarrhea-associated hemolytic uremic syndrome with special reference to histopathologic findings, virulence factors of Shiga toxin-producing Escherichia coli, the host response, and the prothrombotic state. Despite significant advances during the past decade, the exact mechanism by which Shiga toxin-producing E. coli leads to hemolytic uremic syndrome remains unclear. Factors such as Shiga toxin, lipopolysaccharide, the adhesins intimin and E. coli-secreted proteins A, B, and D, the 60-MD plasmid, and enterohemolysin likely contribute to the pathogenesis. Data on the inflammatory response of the host, including leukocytes and inflammatory mediators, are updated. The pathogenesis of the prothrombotic state leading to thrombocytopenia secondary to endothelial cell damage and platelet activation is also discussed. A hypothetical sequence of events from ingestion of the bacteria to the development of full-blown hemolytic uremic syndrome is proposed.

The three-gene paraoxonase family: Physiologic roles, actions and regulation

The paraoxonase (PON) gene family is composed of three members (PON1, PON2, PON3) that share considerable structural homology and are located adjacently on chromosome 7 in humans. By far the most-studied member is PON1, a high-density lipoprotein-associated esterase/lactonase, also endowed with the capacity to hydrolyze organophosphates, but all the three proteins prevent oxidative stress and fight inflammation. They therefore seem central to a wide variety of human illnesses, including atherosclerosis, diabetes mellitus, mental disorders and inflammatory bowel disease. The major goal of this review is to highlight the regulation of each of the paraoxonase components by diverse nutritional molecules and pharmacological agents as well as a number of pathophysiological events, such as oxidative stress and inflammation. Considerable and detailed cell-based studies and animal model experiments have been provided to allow a thorough scrutiny of PON modulation, which will increase our understanding and ability to target these genes in order to efficiently increase their transcriptional activity and decrease the risks of developing different disorders.

Wireless capsule endoscopy for obscure small-bowel disorders: Final results of the first pediatric controlled trial

BACKGROUND AND AIMS Obscure small-bowel disorders are jejunal and ileal lesions undiagnosed by traditional imaging techniques (endoscopic, radiologic). We evaluated the diagnostic usefulness and safety of capsule endoscopy for obscure small-bowel disorders in children and adolescents. METHODS Comparative, prospective, self-controlled trials in patients (age, 10-18 y) suspected to have either small-bowel Crohns disease, polyps, or obscure gastrointestinal (GI) bleeding. Capsule results were compared with the diagnostic imaging studies normally used in this age group. RESULTS Among 20 patients suspected of Crohns disease, multiple lesions consistent with this diagnosis were observed by capsule endoscopy in 50%. Small-bowel Crohns disease was ruled out in 8 patients. Eosinophilic enteropathy was found in 2 others. For polyp detection (n = 6), capsule endoscopy yielded 100% concordance with the control studies when analyzed per patient. However, capsule endoscopy revealed a greater number (50%) of polyps. Among patients with obscure bleeding (n = 4), the capsule examination confirmed a diagnosis of vascular malformations in 3. Capsule endoscopy more accurately identified the precise source of bleeding compared with angiography. All 30 capsule studies were well tolerated, although 1 capsule was retained owing to an inflammatory stenosis. The capsule eventually was expelled after corticosteroid therapy. CONCLUSIONS Capsule endoscopy correctly diagnosed or excluded a bleeding source, small-bowel polyps, or Crohns disease of the small bowel in 29 of 30 patients. Capsule endoscopy permits an accurate, noninvasive approach for diagnosing obscure small bowel lesions in children over the age of 10.

An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy

Background and AimsA substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohns disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy. MethodsTen CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities. ResultsSeventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity. Conclusions6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short-and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.