Richard J. Grand

Common variants at five new loci associated with early-onset inflammatory bowel disease

The inflammatory bowel diseases (IBD) Crohns disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 × 10−9), 22q12 (rs2412973, P = 1.55 × 10−9), 10q22 (rs1250550, P = 5.63 × 10−9), 2q37 (rs4676410, P = 3.64 × 10−8) and 19q13.11 (rs10500264, P = 4.26 × 10−10). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohns disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis.

Intraepithelial eosinophils in esophageal biopsy specimens were noted to be an indicator of prolonged acid reflux. The presence of even a few intraepithelial eosinophils correlated with abnormal acid clearance determined by overnight intraesophageal pH probe study. This new marker also appeared to be an early lesion, as evidence by its presence in children under age 2 yr, and in biopsy specimens from the proximal esophagus where traditional histometric features (basal zone thickening and papillary lengthening) were lacking. Furthermore, when intraepithelial eosinophils were seen in the proximal 75% of the esophagus, they served to identify more severe disease by correlation with greater abnormalities in the pH probe study. Although this new marker is a histologic indication of prolonged acid reflux and may be appreciated in routine endoscopic biopsy specimens in children, it has been observed in patients over 18 yr of age and may be applicable to the adult population.

Comparison of amino acid sequence of troponin I from different striated muscles.

The sequence of troponin I from fast and slow skeletal and cardiac muscle shows strong homology in the region which binds to actin and is responsible for inhibition of the actomyosin ATPase. More differences are found in the N-terminal region which binds to troponin C.

Development of the human gastrointestinal tract: Twenty years of progress

A combination of approaches has begun to elucidate the mechanisms of gastrointestinal development. This review describes progress over the last 20 years in understanding human gastrointestinal development, including data from both human and experimental animal studies that address molecular mechanisms. Rapid progress is being made in the identification of genes regulating gastrointestinal development. Genes directing initial formation of the endoderm as well as organ-specific patterning are beginning to be identified. Signaling pathways regulating the overall right-left asymmetry of the gastrointestinal tract and epithelial-mesenchymal interactions are being clarified. In searching for extrinsic developmental regulators, numerous candidate trophic factors have been proposed, but compelling evidence remains elusive. A critical gene that initiates pancreas development has been identified, as well as a number of genes regulating liver, stomach, and intestinal development. Mutations in genes affecting neural crest cell migration have been shown to give rise to Hirschsprungs disease. Considerable progress has been achieved in understanding specific phenomena, such as the transcription factors regulating expression of sucrase-isomaltase and fatty acid-binding protein. The challenge for the future is to integrate these data into a more complete understanding of the physiology of gastrointestinal development.

Gastrointestinal Manifestations of Cystic Fibrosis: A Review

Cystic fibrosis is the most common, lethal, genetic defect of white populations (1). Once limited largely to infants and children, the immediate prognosis has changed drastically over the last three decades so that now the majority of patients survive into adolescence, and nearly 80% live beyond their twentieth birthdays (2-4). The diagnosis is established in 2% of cases after 18 yr of age. Internal medicine and pediatrics, therefore, now share the complications and consequences of cystic fibrosis. Cystic fibrosis is a genetic syndrome of apparent exocrine dysfunction, characterized by obstructive lesions throughout multi pie-organ systems and disturbances of mucus and electrolyte secretion (5,6). Although reported in various racial groups, cystic fibrosis is more commonly found among whites. It is inherited in an autosomal recessive fashion, and it is estimated to occur in 1:2000 live births (5). The specific genetic defect remains obscure. Elevated concentrations of sweat sodium and chloride are integral and diagnostic features (7). A diversity of symptoms is produced. Cystic fibrosis is a major cause of malabsorption in infants and children in the United States, and it is responsible for a large pro-

High-Dose Pancreatic-Enzyme Supplements and Fibrosing Colonopathy in Children with Cystic Fibrosis

BACKGROUND Fibrosing colonopathy has been reported in young children with cystic fibrosis, the majority of whom take high-strength pancreatic-enzyme supplements to control intestinal malabsorption. We conducted a case-control study in the United States to investigate the relation between dose and type of pancreatic-enzyme supplement and fibrosing colonopathy. METHODS Children with histopathologically confirmed cases of fibrosing colonopathy who required colectomy for colonic strictures from January 1, 1990, through December 31, 1994, were identified. Each of these patients was matched according to age at the time of surgery and medical center with up to four controls with cystic fibrosis who did not have fibrosing colonopathy. RESULTS We studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy (case patients) and 105 controls (mean age, 5.2 years). The mean dose of pancreatic-enzyme supplement was 50,046 units of lipase per kilogram of body weight per day for the case patients and 18,985 units per kilogram per day for the controls. A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy. After adjustment for a history of such complications and the use of these medicines, the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with a dose of 0 to 24,000 units per kilogram per day, was 10.9 (95 percent confidence interval, 1.6 to 71.8), and that associated with a dose of more than 50,000 units per kilogram per day was 199.5 (95 percent confidence interval, 9.9 to 4026.0). The strength, coating, and manufacturer of the products used were not associated with the risk of fibrosing colonopathy. CONCLUSIONS In young children with cystic fibrosis, we found a strong relation between high daily doses of pancreatic-enzyme supplements and the development of fibrosing colonopathy. Our findings support recommendations that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.

Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy

Drucy S. Borowitz, MD, Richard J. Grand, MD, Peter R. Durie, MD, and the Consensus Committee a From the Department of Pediatrics, State University of New York at Buffalo, and the Division of Pediatric Pulmonology, Childrens Hospital of Buffalo; the Department of Pediatrics, Tufts University School of Medicine, and the Division of Pediatric Gastroenterology and Nutrition, New England Medical Center, Boston, Massachusetts; and the Department of Pediatrics, University of Toronto, and the Division of Pediatric Gastroenterology.and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada

Nutritional basis of growth failure in children and adolescents with Crohn's disease.

In order to investigate the mechanisms of severe growth failure in children with Crohns disease, 7 affected patients (ages 9–17 yr) were studied before, during, and after parenteral nutrition as a supplement to oral intake. At the time of entrance into the study, patients had had cessation of linear growth for at least 1 yr, or a decrease of one standard deviation in height percentiles and/or a bone-age delay greater than 2 yr. Nutritional status was evaluated in all patients, and endocrinologic and metabolic balance studies were performed in 5 of the 7 pa tients. Neither endocrine dysfunction nor malabsorption accounted for the severe growth failure. Patients received approximately 8 wk of combined oral and parenteral nutrition achieving at least 75 calories per kilogram per day or greater. Weight gain averaged 4.8 ± 1.6 kg, while total body potassium (indicative of lean body mass) demonstrated a parallel significant rise (P

Vitamin D Status in Children and Young Adults With Inflammatory Bowel Disease

OBJECTIVES. Previous studies of vitamin D status in pediatric patients with inflammatory bowel disease have revealed conflicting results. We sought to report (1) the prevalence of vitamin D deficiency (serum 25-hydroxy-vitamin D concentration ≤15 ng/mL) in a large population with inflammatory bowel disease, (2) factors predisposing to this problem, and (3) its relationship to bone health and serum parathyroid hormone concentration. PATIENTS AND METHODS. A total of 130 patients (8–22 years of age) with inflammatory bowel disease, 94 with Crohn disease and 36 with ulcerative colitis, had serum 25-hydroxy-vitamin D, intact parathyroid hormone, and lumbar spine bone mineral density (using dual-energy x-ray absorptiometry) measured at Children’s Hospital Boston. RESULTS. The prevalence of vitamin D deficiency was 34.6%. Mean serum 25-hydroxy-vitamin D concentration was similar in patients with Crohn disease and ulcerative colitis, 52.6% lower among patients with dark skin complexion, 33.4% lower during the winter months (December 22 to March 21), and 31.5% higher among patients who were taking vitamin D supplements. Serum 25-hydroxy-vitamin D concentration was positively correlated with weight and BMI z score, disease duration, and serum albumin concentration and negatively correlated with erythrocyte sedimentation rate. Patients with Crohn disease and upper gastrointestinal tract involvement were more likely to be vitamin D deficient than those without it. Serum 25-hydroxy-vitamin concentration was not associated with lumbar spine bone mineral density z score or serum parathyroid hormone concentration. CONCLUSIONS. Vitamin D deficiency is highly prevalent among pediatric patients with inflammatory bowel disease. Factors predisposing to the problem include having a dark-skin complexion, winter season, lack of vitamin D supplementation, early stage of disease, more severe disease, and upper gastrointestinal tract involvement in patients with Crohn disease. The long-term significance of hypovitaminosis D for this population is unknown at present and merits additional study.

Impaired Intestinal Iron Absorption in Crohn’s Disease Correlates with Disease Activity and Markers of Inflammation

Background Anemia in patients with Crohns disease (CD) is a common problem of multifactorial origin, including blood loss, malabsorption of iron, and anemia of inflammation. Anemia of inflammation is caused by the effects of inflammatory cytokines [predominantly interleukin‐6 (IL‐6)] on iron transport in enterocytes and macrophages. We sought to elucidate alterations in iron absorption in pediatric patients with active and inactive CD. Methods Nineteen subjects with CD (8 female, 11 male patients) were recruited between April 2003 and June 2004. After an overnight fast, serum iron and hemoglobin levels, serum markers of inflammation [IL‐6, C‐reactive protein (CRP), and erythrocyte sedimentation rate], and a urine sample for hepcidin assay were obtained at 8 am. Ferrous sulfate (1 mg/kg) was administered orally, followed by determination of serum iron concentrations hourly for 4 hours after the ingestion of iron. An area under the curve for iron absorption was calculated for each patient data set. Results There was a strong inverse correlation between the area under the curve and IL‐6 (P = 0.002) and area under the curve and CRP levels (P = 0.04). Similarly, the difference between baseline and 2‐hour serum iron level (&Dgr;[Fe]2hr) correlated with IL‐6 (P = 0.008) and CRP (P = 0.045). When cutoff values for IL‐6 (>5 pg/mL) and CRP (>1.0 mg/dL) were used, urine hepcidin levels also positively correlated with IL‐6 and CRP levels (P = 0.003 and 0.007, respectively). Conclusions Subjects with active CD have impaired oral iron absorption and elevated IL‐6 levels compared with subjects with inactive disease. These findings suggest that oral iron may be of limited benefit to these patients. Future study is needed to define the molecular basis for impaired iron absorption.