Peter M. Gillett

Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.

Introduction: The incidence of early‐onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early‐onset IBD population. Patients and Methods: 906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case‐control analysis and detailed genotype‐phenotype analysis were performed. Results: The Leu1007finsC variant was associated with susceptibility to CD by case‐control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5‐14.7]). Conclusions: These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.

Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth indices in early onset inflammatory bowel disease

Background and aims: The OCTN1 (SLC22A4 1672C→T) and OCTN2 (SLC22A5 −207G→C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn’s disease (CD), but their contribution in children has not been examined. Methods: These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a_1, IGR2198a_1, and IGR2230a_1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls. Results: All SNPs were in strong linkage disequilibrium (D′ >0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (p<0.04). The homozygous mutant OCTN1/2 haplotype was increased in IBD (24.3% v 16.1%, p = 0.02) and UC (28.2% v 16.1%, p = 0.02) compared with controls. The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility. Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight, height, and BMI centile (<9th centile) at diagnosis (weight: 87.9% v 67.3% (p = 0.002), odds ratio (OR) = 3.52 (95% confidence interval, 1.51 to 8.22); height: 84.1% v 68.4% (p<0.05), OR = 2.44 (1.00 to 5.99); BMI: 79.6% v 61.1% (p = 0.02), OR = 2.49 (1.14 to 5.44)), and lower weight centile at follow up (87.5% v 64.6% (p = 0.03), OR = 3.83 (1.03 to 14.24)). Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis (p = 0.02, OR = 3.41 (1.20 to 9.66)). Conclusions: These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis.

IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland

The discovery of NOD2/CARD15 as the first susceptibility gene in Crohn’s disease has contributed significantly to a fundamental change in the direction of basic research in inflammatory bowel disease (IBD), triggering renewed interest in the integrity of the innate immune response in IBD and appropriate orchestration of a subsequent adaptive immune response.1,2 More widely, in all complex diseases this finding in 2001 provided a much welcomed and needed proof of principle for non-parametric linkage analysis. Another study with major implications for the pathogenesis of Crohn’s disease as well as for investigation of all complex disorders has recently been published.3 The North American consortium performed an association study testing 308 332 markers spanning the entire genome in 567 patients with ileal Crohn’s disease and 571 controls of non-Jewish European ancestry. Of the three markers reported to retain significance after stringent Bonferroni correction, two were located in the NOD2/CARD15 gene. The third marker (rs11209026) was a non-synonymous variant in the interleukin-23 receptor (IL23R) gene on chromosome 1p31. Replication was obtained in the index paper in a Jewish ancestry case-control analysis of patients with Crohn’s disease by transmission disequilibrium testing in 883 families with offspring affected by IBD and in a combined case-control analysis …

Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children

The revised BSPGHAN guidelines for the diagnosis and management of coeliac disease represent an important shift in diagnostic strategy, aimed at simplifying and shortening the diagnostic process in selected cases. Guidance is given concerning the indications for testing for coeliac disease, which is still significantly underdiagnosed in the UK. While screening data suggest a likely incidence of 1 in 100 persons, only 10%–20% of this figure is currently being diagnosed.The BSPGHAN guidelines follow the new ESPGHAN guidelines in overall diagnostic strategy, while providing more didactic stratagems, which should be of assistance for paediatricians in specialties other than gastroenterology.

The Diagnostic Accuracy of Fecal Calprotectin During the Investigation of Suspected Pediatric Inflammatory Bowel Disease

OBJECTIVES:Fecal calprotectin (FC) is elevated in patients with inflammatory bowel disease (IBD). Studies evaluating FC during the initial investigation of children with suspected IBD have been limited, especially with regard to their small patient groups. We aimed to evaluate the diagnostic accuracy of FC in a large regional cohort of children undergoing full upper and lower endoscopy for suspected IBD, comparing FC with six common blood parameters.METHODS:Using a retrospective case–control design all FC measurements carried out between 2005 and 2010 in children <18 years old were obtained. All IBD and non-IBD patients who had a FC measurement available before full endoscopic evaluation for suspected bowel inflammation were examined. FC was measured using the PhiCal Test. Multivariate analyzes and receiver operating characteristic curve generation were used to derive significance.RESULTS:A total of 190 patients (91 IBD and 99 non-IBD controls) met the inclusion criteria. Median FC at diagnosis for the IBD group was 1,265 μg/g (interquartile range (IQR) 734–2,024 μg/g), compared with 65 μg/g (IQR 20–235 μg/g) in controls (P<0.001). FC levels did not vary significantly between patients with Crohns disease, ulcerative colitis, and IBD unclassified and were not influenced by age or disease location. FC was found to be far superior to commonly utilized blood parameters such as C-reactive protein and white cell count (both P<0.01), with an area under the curve of 0.93 (95% confidence interval 0.89–0.97).CONCLUSIONS:This study demonstrates that FC is an invaluable tool in determining those children who may require endoscopy for suspected IBD, and elevated values should prompt further investigation.

Totally implantable central venous access devices for paediatric oncology patients

BACKGROUND Totally implantable central venous access devices (ports) have been available for over 10 years but have not achieved widespread use in paediatric oncology patients. We reviewed our experience with these devices over 9 years to assess their safety and acceptability. PROCEDURE We conducted a retrospective review of insertion technique and reasons for removal of all ports placed in paediatric oncology patients in this hospital between 1989 and 1996, with follow-up until 1998. Acceptability of both ports and external catheters was assessed by a questionnaire in a subgroup of families attending the oncology clinic. RESULTS One hundred forty-nine ports were inserted during the study period. The median catheter life was 399 days (4-1,406), with a total of 69,342 catheter days. Sixty-nine percent of ports were removed electively at the end of treatment; 8% required removal because of infection and 5% because of blockage. No ports were accidentally dislodged or damaged. Children experienced significantly less restriction of activity with a port compared to an external catheter and greatly preferred the cosmetic appearance. The need for needle insertion to access the port was not seen as a disadvantage by most families. CONCLUSIONS Ports can provide satisfactory central venous access for the majority of paediatric oncology patients, with a low risk of line-related complications and a high degree of acceptability to children and their parents.

Vertical Transmission of Hepatitis C Virus Infection

Since the virus responsible for non-A, non-B hepatitis was cloned in 1989, much has been learnt about the epidemiology, diagnosis and clinical spectrum of hepatitis C virus (HCV) infection. As the routes of transmission are elucidated, specific groups of children as well as adults are known to be at particular risk of infection. The women most at risk of HCV infection are those with a history of injecting drug use. Mother-to-child transmission has been documented, although the exact risk has not been quantified, and the factors influencing the risk remain to be evaluated. This article reviews current knowledge on vertical transmission of HCV, and provides some guidelines on the management of infants born to women infected with the virus.

The rising incidence of celiac disease in Scotland.

BACKGROUND AND OBJECTIVES: Although the incidence of pediatric celiac disease (CD) is increasing globally, it is uncertain whether this is attributed to improved case ascertainment or signifies a true rise. We aimed to identify all incident cases of childhood CD in southeast Scotland over the period 1990 to 2009 to assess trends in total incidence and cases diagnosed as a result of (1) a classic presentation, (2) a nonclassic presentation, or (3) targeted screening. METHODS: Twenty-year retrospective cohort study of case notes, pathology databases, endoscopy, and patient records for all children (<16 years of age) diagnosed with CD on biopsy in southeast Scotland (at-risk population of 225 000–233 000). Data were age-gender standardized and Poisson regression models used to calculate changes in incidence over time. RESULTS: A total of 266 children were diagnosed from 1990 to 2009 with an increase in incidence from 1.8/100 000 (95% confidence interval [CI] 1.1–2.7) to 11.7/100 000 (95% CI 9.8–13.9) between the epochs 1990 to 1994 and 2005 to 2009, respectively (P < .0001). The incidence of nonclassic presentation (children with a monosymptomatic presentation and those with extraintestinal symptoms) and actively screened cases increased by 1566% (P < .05) and 1170% (P < .001) from 1990 to 1999 to 2000 to 2009, respectively. However, a rise in the incidence of Oslo classic cases from 1.51/100 000 (95% CI 0.91–2.38) in 1990 to 1994 to 5.22/100 000 (95% CI 3.98–6.75) in 2005 to 2009 (P < .01) remained evident. CONCLUSIONS: The incidence of pediatric CD increased 6.4-fold over the 20 years. This study demonstrates that this rise is significant for classic CD, indicating a true rise in the incidence of pediatric CD.

Autophagy Gene ATG16L1 Influences Susceptibility and Disease Location but Not Childhood-Onset in Crohn's Disease in Northern Europe

Background: The rs2241880A/G variant of the ATG16L1 gene has been associated with susceptibility to ileal Crohns disease (CD) in adults. Our aim was to assess whether germline variation of ATG16L1 acts as an independent determinant of susceptibility to childhood‐onset CD in the high‐incidence Scottish population. Methods: In all, 2195 subjects (361 children (inflammatory bowel disease [IBD] diagnosis <17 years), their parents (n = 634), 855 adult IBD patients, and 345 controls were genotyped. Case‐control analysis was powered to detect effect sizes with an odds ratio (OR) >1.39 in pediatric CD. Case‐control analysis, transmission disequilibrium testing (TDT), analysis of variance (ANOVA) of growth parameter z‐scores, Kruskal–Wallis test (age at diagnosis), and multifactorial genotype–phenotype analysis (Montreal classification) were performed. 7.8% of pediatric CD patients and 37.2% of adult CD patients had pure ileal disease. Results: We confirmed the association of the rs2241880G‐allele with adult‐onset CD (60.7% versus controls 53.9%, P = 0.01, OR 1.32, 95% confidence interval [CI] 1.07–1.63) in contrast to childhood‐onset CD (54.1% versus controls, P = 0.95, OR 1.01, 95% CI 0.80–1.26). TDT analysis was negative. Genotype–phenotype analysis demonstrated an association of pure ileal disease with the rs2241880G‐allele (P = 0.02, OR 1.34, 95% CI 1.03–1.74). Using binary logistic regression analysis we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (P = 0.03, OR 2.43, 95% CI 1.05–5.65). ATG16L1 genotype did not influence age at CD diagnosis. ANOVA of z‐scores of height, weight, and body mass index (BMI) at CD diagnosis in children showed no association with genotype. Conclusions: The ATG16L1 variant is associated with susceptibility to adult CD in Scotland, but not early‐onset disease. These contrasting effects are primarily driven by differences in disease location between early‐onset and adult‐onset disease.

Fecal Calprotectin Complements Routine Laboratory Investigations in Diagnosing Childhood Inflammatory Bowel Disease

Background: We aimed to study fecal calprotectin in Scottish children with inflammatory bowel disease (IBD) and compare its diagnostic accuracy with blood parameters. Methods: Stool samples from 48 Scottish children (29 males, 19 females) had calprotectin measured at IBD diagnosis. The median age at diagnosis was 11.2 years (interquartile range [IQR] 8.7–13.0 years). There were 33 patients with Crohns disease, 5 with ulcerative colitis, and 10 with IBD type unspecified. IBD was diagnosed by standard criteria. Calprotectin was measured using a commercially available kit (PhiCal Test) and 47/48 patients had comparative blood results available at diagnosis. Results: The fecal calprotectin concentrations were raised in 96% (46/48) of patients studied. The median calprotectin value was 750 &mgr;g/g (IQR 235.8–1251 &mgr;g/g). In comparison with standard blood tests, 32/45 (71.1%) had abnormal erythrocyte sedimentation rate, 19/38 (50.0%) had abnormal C‐reactive protein, 29/46 (63.0%) had raised platelets, 12/45 (26.7%) had hypoalbuminemia, and 38/46 (82.6%) had abnormal hemoglobin. We identified 7/47 (14.9%) patients with raised calprotectin at diagnosis who did not have any abnormalities detected in the blood tests performed. All 48 patients (100%) had at least 1 abnormal blood test and/or raised calprotectin at diagnosis. Conclusions: Calprotectin is significantly more likely to be raised than any commonly employed blood tests at IBD diagnosis. When used in combination with these bloods tests an abnormality was demonstrated in 1 or both tests in all patients at diagnosis in this study. Fecal calprotectin measurement is a significant advance when used contemporaneously and in addition to a routine panel of blood tests in the diagnosis of pediatric IBD.