Marion Rowland

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.

Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity

To cite this article: Kezic S, O’Regan GM, Yau N, Sandilands A, Chen H, Campbell LE, Kroboth K, Watson R, Rowland M, Irwin McLean WH, Irvine AD. Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity. Allergy 2011; 66: 934–940.

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.

Raman profiles of the stratum corneum define 3 filaggrin genotype–determined atopic dermatitis endophenotypes

Background Filaggrin (FLG) has a central role in the pathogenesis of atopic dermatitis (AD). FLG is a complex repetitive gene; highly population-specific mutations and multiple rare mutations make routine genotyping complex. Furthermore, the mechanistic pathways through which mutations in FLG predispose to AD are unclear. Objectives We sought to determine whether specific Raman microspectroscopic natural moisturizing factor (NMF) signatures of the stratum corneum could be used as markers of FLG genotype in patients with moderate-to-severe AD. Methods The composition and function of the stratum corneum in 132 well-characterized patients with moderate-to-severe AD were assessed by means of confocal Raman microspectroscopy and measurement of transepidermal water loss (TEWL). These parameters were compared with FLG genotype and clinical assessment. Results Three subpopulations closely corresponding with FLG genotype were identified by using Raman spectroscopy. The Raman signature of NMF discriminated between FLG-associated AD and non–FLG-associated AD (area under the curve, 0.94; 95% CI, 0.91-0.99). In addition, within the subset of FLG-associated AD, NMF distinguished between patients with 1 versus 2 mutations. Five novel FLG mutations were found on rescreening outlying patients with Raman signatures suggestive of undetected mutations (R3418X, G1138X, S1040X, 10085delC, and L2933X). TEWL did not associate with FLG genotype subgroups. Conclusions Raman spectroscopy permits rapid and highly accurate stratification of FLG-associated AD. FLG mutations do not influence TEWL within established moderate-to-severe AD.

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

One week treatment for Helicobacter pylori infection.

Helicobacter pylori is associated with primary antral gastritis, duodenal ulceration, and gastric cancer. Current regimens for treating infection in children using bismuth and antibiotics for two to six weeks are cumbersome. The aim of this study was to evaluate a one week course of treatment. All children undergoing endoscopy were assessed for the presence of H pylori by culture, histology, rapid urease test, and 13C urea breath test. Infected children received a one week course of colloidal bismuth subcitrate 480 mg/1.73 m2/day (maximum 120 mg four times a day), combined with metronidazole 20 mg/kg/day (maximum 200 mg three times a day), and clarithromycin 15 mg/kg/day (maximum 250 mg twice a day). To optimise compliance, drugs were dispensed in a ‘Redidose’ box containing a compartment for each day, and subcompartments marked ‘breakfast’, ‘lunch’, ‘dinner’, and ‘bedtime’. Compliance and side effects were assessed immediately after treatment. A urea breath test was performed at least one month after treatment. Twenty two children infected with H pylori were entered into the study; 20 of these took all doses; two children suffered significant side effects (diarrhoea and vomiting). H pylori was eradicated in 21 of the 22 children (95.45%; 95% confidence interval 77% to 100%). This study shows that H pylori infection in children can be cleared by a one week course of treatment.

Effect of Helicobacter pylori eradication on the natural history of duodenal ulcer disease

BACKGROUND Duodenal ulcer disease is strongly associated with Helicobacter pylori infection of the gastric mucosa. Eradication of H pylori from the gastric mucosa in adults is associated with long term healing of ulcers. AIMS To follow a cohort of children with duodenal ulcer disease for a minimum of two years after the eradication ofH pylori. PATIENTS AND METHODS Over a three year period, all children diagnosed with duodenal ulcer disease had their symptoms documented and their H pylori status evaluated. The histories of these children were carefully screened to determine previous symptoms and to document previous treatment regimens. RESULTS Sixteen children were diagnosed with ulcers and 15 were available for treatment and long term follow up. The median age at which symptoms first occurred was 10.5 years (range, 6–14) and the median duration of symptoms was 24 months (range, 2–60). Ten of the children had been treated with H2receptor antagonists for a median of 3.5 months (range, 1–60). Duodenal ulcers healed in all children after eradication of H pylori and all children have remained asymptomatic for a median of 37 months (range, 26–62). No child has required subsequent admission to hospital. CONCLUSION Eradication of H pylori is very effective in the long term healing of duodenal ulcer disease.H pylori eradication should be the standard treatment for all infected children who present with duodenal ulcer disease.

Outcome in Cystic Fibrosis Liver Disease

OBJECTIVES:Evidence suggests that cystic fibrosis liver disease (CFLD) does not affect mortality or morbidity in patients with cystic fibrosis (CF). The importance of gender and age in outcome in CF makes selection of an appropriate comparison group central to the interpretation of any differences in mortality and morbidity in patients with CFLD.METHODS:This is a 7-year follow-up of 42 children with CFLD and their age- and sex-matched controls. Participants were reviewed clinically, biochemically, and radiologically at follow-up.RESULTS:Overall, 85% (72 of 84) of the original cohort were included, 36 CFLD participants and 36 CF controls. There was no significant difference in the number of deaths/transplants between groups (7 of 36 (19.4%) CFLD participants, 3 of 36 (8.3%) CF controls). There was a tendency for participants with CFLD to die younger than their respective CF controls. There was no difference in height, weight, body mass index, or pulmonary function between the groups. Nutritional parameters (sum skinfold thickness 31.6 vs. 42.3, P=0.03; mean upper arm fat area 15.08 vs. 10.59, P=0.001; Shwachman score 43.7 vs. 32.1, P=0.001) were worse among CFLD participants than among CF controls. Cystic fibrosis-related diabetes was more common in CFLD participants (11 of 27 (40.7%) vs. 5 of 33 (15.2%), P=0.02). Eight children (22.2%) with evidence of CFLD at baseline had no clinical evidence of liver disease as adults.CONCLUSIONS:Patients with CFLD have a more severe CF phenotype than do CF patients without liver disease. However, a subgroup of children with CFLD will not manifest clinically significant liver disease as adults.

The incidence of cyclic vomiting syndrome in children: population-based study.

OBJECTIVE:Cyclic vomiting syndrome (CVS) is characterized by severe recurrent episodes of vomiting in an otherwise healthy child. Currently, there is no population data on the incidence of CVS. The aim of this study was to determine the incidence of CVS and to define the clinical characteristics of the condition at diagnosis.METHODS:Each pediatrician on the island of Ireland was surveyed on a monthly basis from January 1, 2005 to December 31, 2005 by the Irish Pediatric Surveillance Unit (IPSU) and was asked to report any incident cases of CVS according to the criteria outlined by the First International Symposium on CVS. Subsequently, data on demographics and clinical features were collected anonymously from the reporting pediatricians.RESULTS:Eighty-nine percent (1,647 of 1,848) of the surveillance cards were returned, reporting 41 valid cases of CVS. The incidence of CVS in Ireland was 3.15/100,000 children per annum for 2005 (95% confidence interval [CI] 2.19–4.11). The median age at diagnosis of CVS was 7.42 yr (range 1.8–15 yr). The median age at onset of CVS was 4 yr (range 0.5–14 yr) with 46% (19 of 41) of children having an onset at or before the age of 3 yr. The median number of episodes of CVS per child per year was eight (range 3–52); the median duration of an episode was 24 h (range 1 h to 5 days). Of school-age children, 85% (22 of 26) had missed school in the previous year due to CVS and 44% (18 of 41) were admitted to hospital for supportive treatment or investigation of CVS.CONCLUSION:CVS is a relatively common condition in pediatric patients, with an incidence comparable to other major gastrointestinal diseases of childhood, such as Crohns disease. The onset of pediatric CVS is generally early in childhood and this disease causes significant morbidity in the majority of those affected.