Billy Bourke

Genetic Modifiers of Liver Disease in Cystic Fibrosis

CONTEXT A subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension. OBJECTIVE To assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF. DESIGN, SETTING, AND PARTICIPANTS Two-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD. MAIN OUTCOME MEASURES Differences in distribution of genotypes in patients with CFLD vs patients without CFLD. RESULTS The initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)). CONCLUSIONS The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Focally enhanced gastritis in children with Crohn's disease and ulcerative colitis

OBJECTIVES:Focally enhanced gastritis (FEG) has been suggested as a specific diagnostic marker for patients with Crohns disease. However, the utility of FEG for distinguishing Crohns disease from ulcerative colitis is uncertain in adults, and the occurrence of this lesion in children has not been defined. The aim of this study was to evaluate the occurrence of FEG and other gastric histological abnormalities in children with inflammatory bowel disease (IBD) and to examine the utility of FEG in discriminating between ulcerative colitis and Crohns disease.METHODS:This is a retrospective, case-controlled study of upper GI histopathological findings in children with IBD. Gastric histopathology was defined and graded according to the Updated Sydney System.RESULTS:FEG was present in 28 of 43 (65.1%) children with Crohns disease and five of 24 (20.8%) children with ulcerative colitis, compared to three of 132 (2.3%) children without IBD or one of 39 (2.6%) children with Helicobacter pylori infection. There were no differences between those with and without FEG with regard to upper GI symptoms or previous anti-inflammatory drug ingestion (5-aminosalicylic acid compounds or steroids). All patients with H. pylori infection had chronic antral gastritis, but only one child with H. pylori had FEG. In addition, mild to moderate chronic gastritis was present in 15 of 43 (34.9%) children with Crohns disease and in 12 of 24 (50%) patients with ulcerative colitis.CONCLUSIONS:The presence of FEG suggests underlying IBD. Although FEG is particularly common in children with Crohns disease, it does not reliably differentiate between Crohns disease and ulcerative colitis.

A Prospective Study of the Oral Manifestations of Crohn's Disease

BACKGROUND & AIMS Recent studies suggest that the mouth may be involved frequently in patients with Crohns disease (CD). The aim of this study was to document prospectively the proportion of children with oral lesions at diagnosis of CD, to describe the type of lesions found, and to examine the ability of gastroenterologists to identify correctly oral Crohns manifestations. METHODS In a prospective 3-year study, systematic dental examinations were performed on all children with suspected inflammatory bowel disease. Each child underwent upper endoscopy, colonoscopy, and barium follow-through radiography. RESULTS Forty-eight of 49 children with CD were examined by the dentist. Oral CD was found in 20 patients (41.7%). Oral findings included mucogingivitis (12 patients), mucosal tags (4 patients), deep ulceration (4 patients), cobblestoning (3 patients), lip swelling (3 patients), and pyostomatitis vegetans (1 patient). Noncaseating granulomas were found in all 8 oral biopsy specimens from oral CD lesions (100%). Two patients with granulomas in oral biopsy specimens had no granulomas found in any other biopsy specimens. The presence of oral manifestations was associated with perianal disease. In only 9 patients (45%) with oral CD was the mouth found to be abnormal by the consultant gastroenterologists. Only nonspecific oral changes were seen in children with ulcerative colitis and indeterminate colitis. CONCLUSIONS More than one third of all children presenting with CD had involvement of the mouth. The ability of physicians to recognize oral lesions was poor. Expert dental evaluation may be useful during the investigation of patients with suspected inflammatory bowel disease.

A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease

Aliment Pharmacol Ther 2011; 33: 946–953

Mucosal Reactive Oxygen Species Decrease Virulence by Disrupting Campylobacter jejuni Phosphotyrosine Signaling

Reactive oxygen species (ROS) play key roles in mucosal defense, yet how they are induced and the consequences for pathogens are unclear. We report that ROS generated by epithelial NADPH oxidases (Nox1/Duox2) during Campylobacter jejuni infection impair bacterial capsule formation and virulence by altering bacterial signal transduction. Upon C. jejuni invasion, ROS released from the intestinal mucosa inhibit the bacterial phosphotyrosine network that is regulated by the outer-membrane tyrosine kinase Cjtk (Cj1170/OMP50). ROS-mediated Cjtk inactivation results in an overall decrease in the phosphorylation of C. jejuni outer-membrane/periplasmic proteins, including UDP-GlcNAc/Glc 4-epimerase (Gne), an enzyme required for N-glycosylation and capsule formation. Cjtk positively regulates Gne by phosphorylating an active site tyrosine, while loss of Cjtk or ROS treatment inhibits Gne activity, causing altered polysaccharide synthesis. Thus, epithelial NADPH oxidases are an early antibacterial defense system in the intestinal mucosa that modifies virulence by disrupting bacterial signaling.

Looking in the mouth for Crohn's disease

Abstract: It is widely acknowledged among gastroenterologists that the oral cavity may be involved in Crohns disease (CD). However, the specific manifestations are poorly appreciated. Although oral aphthous ulceration is probably not diagnostically useful in patients with suspected CD, disease‐specific manifestations do occur and are particularly common in children presenting with CD. These manifestations can be subtle, often are subclinical, yet commonly harbor diagnostically useful material (granulomas). Orofacial granulomatosis (OFG) is conventionally used to describe patients with overt oral disease without obvious involvement of the gastrointestinal tract. However, many patients with OFG have subclinical intestinal CD or will progress to develop overt intestinal CD with time. The management of severe oral disease is challenging and lacks a clear evidence base. Inflamm Bowel Dis 2009

Rapid rise in incidence of Irish paediatric inflammatory bowel disease

Aims To describe the change in incidence of paediatric inflammatory bowel disease (IBD) observed at the National Centre for Paediatric Gastroenterology, Hepatology and Nutrition, and to determine whether the presenting disease phenotype and disease outcomes have changed during the past decade. Methods The annual incidence of IBD in Irish children aged <16 years was calculated for the years 2000–2010. Two subsets of patients, group A (diagnosed between 1 January 2000 and 31 December 2001), and group B (diagnosed between 1 January and 31 December 2008) were phenotyped according to the Paris Classification. Phenotype at diagnosis and 2-year follow-up were then compared. Results 406 new cases of IBD were identified. The incidence was 2.5/100 000/year in 2001, 7.3 in 2008 and 5.6 in 2010, representing a significant increase in the number of new cases of Crohns disease (CD) and ulcerative colitis (UC). There were 238 cases of CD; 129 of UC; and 39 of IBD unclassified. Comparing groups A and B, no differences were found in disease location at diagnosis or, for CD, in its behaviour. Conclusions There has been a substantial and sustained increase in the incidence of childhood UC and CD in Ireland over a relatively short period of time. However, disease phenotype at diagnosis has not changed. At 2 years follow-up, CD appears to progress less frequently than in some neighbouring countries. These variations remain unexplained. Prospective longitudinal studies will help to elucidate further the epidemiology of childhood IBD.

Interaction of Cryptosporidium hominis and Cryptosporidium parvum with Primary Human and Bovine Intestinal Cells

ABSTRACT Cryptosporidiosis in humans is caused by the zoonotic pathogen Cryptosporidium parvum and the anthroponotic pathogen Cryptosporidium hominis. To what extent the recently recognized C. hominis species differs from C. parvum is unknown. In this study we compared the mechanisms of C. parvum and C. hominis invasion using a primary cell model of infection. Cultured primary bovine and human epithelial intestinal cells were infected with C. parvum or C. hominis. The effects of the carbohydrate lectin galactose-N-acetylgalactosamine (Gal/GalNAc) and inhibitors of cytoskeletal function and signal transduction mechanisms on entry of the parasites into host cells were tested. HCT-8 cells (human ileocecal adenocarcinoma cells) were used for the purpose of comparison. Pretreatment of parasites with Gal/GalNAc inhibited entry of C. parvum into HCT-8 cells and primary bovine cells but had no effect on entry of either C. parvum or C. hominis into primary human cells or on entry of C. hominis into HCT-8 cells. Both Cryptosporidium species entered primary cells by a protein kinase C (PKC)- and actin-dependent mechanism. Staurosporine, in particular, attenuated infection, likely through a combination of PKC inhibition and induction of apoptosis. Diversity in the mechanisms used by Cryptosporidium species to infect cells of different origins has important implications for understanding the relevance of in vitro studies of Cryptosporidium pathogenesis.

Liquid paraffin: a reappraisal of its role in the treatment of constipation

Liquid paraffin or mineral oil is a transparent, colourless, odourless, or almost odourless, oily liquid composed of saturated hydrocarbons obtained from petroleum.1 Petroleum was used as a medicine at least 400 years before Christ.2 The earliest internal use of refined petroleum appears to date back to 1872, when Robert A. Chesebrough was granted a patent for the manufacture of “a new and useful product from petroleum”.2 The use of liquid paraffin gained popularity, after Sir W. Arbuthnot Lane, Chief Surgeon of Guys Hospital in 1913, recommended its use as a treatment for intestinal stasis and chronic constipation.3 The popularity of liquid paraffin as a treatment for constipation and encopresis stems primarily from its tolerability and ease of titration. Although conversion of mineral oil to hydroxy fatty acids induces an osmotic effect,4 liquid paraffin appears to work primarily as a stool lubricant.5 Therefore, liquid paraffin is not associated with abdominal cramps, diarrhoea, flatulence, electrolyte disturbances, or the emergence of tolerance with long term usage, side effects commonly associated with osmotic or stimulant laxatives.6 These features make liquid paraffin particularly attractive for use in chronic constipation and encopresis of childhood, where large doses and prolonged administration commonly are necessary during the disimpaction and maintenance phases of treatment, respectively.6 However, although liquid paraffin is widely accepted and recommended as a fundamental component of regimens for the management of constipation in North America and Australia,6 7 it is little used in the United Kingdom.8 9 This trans-Atlantic dichotomy in liquid paraffin usage has been underscored by the American Academy of Pediatrics (AAP) endorsement of practice guidelines developed by the North American Society for Pediatric Gastroenterology and Nutrition (NASPGN) for the management of constipation in infants and children.6 NASPGN clearly identify liquid paraffin (mineral …

Byler-like familial cholestasis in an extended kindred.

Progressive familial intrahepatic cholestasis (PFIC) occurs in many communities and races. A form of PFIC in five children from two consanguineous marriages in an Irish kindred is described. In addition, a review of clinical information from the records of three deceased members of the kindred strongly implies that they also suffered from PFIC. The children had a history of neonatal diarrhoea, sepsis, and intermittent jaundice that ultimately became permanent. They suffered intractable pruritus and growth retardation. Despite evidence of severe cholestasis, serum gamma-glutamyl transferase and cholesterol were normal in these children. Sweat sodium concentration were raised in three children. Liver histology showed severe intrahepatic cholestasis and hepatocellular injury. Urinary bile acid analysis revealed a non-specific pattern consistent with chronic cholestasis. These children suffer from a form of PFIC remarkably similar to that occurring in members of the Byler kindred.