Richard A. Schreiber

Inflammatory Bowel Disease in the South Asian Pediatric Population of British Columbia

BACKGROUND:Geographical differences, population migration, and changing demographics suggest an environmental role in prevalence, modulation, and phenotypic expression of inflammatory bowel disease (IBD).AIM:To determine the incidence of IBD and disease subtype in the pediatric South Asian population in British Columbia (BC) compared with non-South Asian IBD patients in the same geographic area.METHODS:Chart review with data collected for all patients ≤16 yr of age diagnosed with IBD at B.C. Childrens hospital, January 1985 to June 2005. Age, gender, family history, duration of symptoms, type, and extent of disease were extracted. Identified South Asian subjects were prospectively interviewed.RESULTS:Seventy-five South Asian patients were diagnosed with IBD, 48% Crohns disease (CD), 33.3% ulcerative colitis (UC), and 18.7% with indeterminate colitis (IC), in contrast to 71%, 18.8%, and 10.2%, respectively, in the non-South Asian population. The incidence rate for South Asian IBD patients, for the period 1996–2001 was 15.19/105 (6.41/105 for CD, 6.70/105 for UC, and 2.08/105 for IC) compared with 5.19/105 for the non-South Asian IBD group (3.69/105, 0.96/105, and 0.54/105, respectively). The South Asian male/female ratio was significantly different from that observed for the rest of the population.CONCLUSION:These data suggest a significantly higher incidence of IBD in the South Asian pediatric population compared with the rest of the BC pediatric population, with a different pattern of phenotypic expression, a male predominance, and more extensive colonic disease. These data suggest a potential effect of migration, and environmental and lifestyle change on the incidence of IBD and disease subtype.

Vascular abnormalities in Adams-Oliver syndrome : Cause or effect?

We describe a young girl diagnosed with the Adams-Oliver syndrome (AOS) associated with double outlet right ventricle, portal hypertension, and pulmonary hypertension. We hypothesize that a congenital vascular abnormality is the underlying pathogenesis and that the cutaneous defects characteristically seen in AOS represent the most common manifestation of this. We suggest that AOS should not merely be considered a syndrome consisting of aplasia cutis congenita and terminal transverse limb defects but rather a constellation of clinical findings resulting from an early embryonic vascular abnormality.

Diagnosing autoimmune hepatitis in children: Is the International Autoimmune Hepatitis Group scoring system useful?

BACKGROUND & AIMS In 1999, the International Autoimmune Hepatitis Group (IAIHG) modified a scoring system to differentiate adult patients with definite or probable autoimmune hepatitis (AIH) from those with other forms of chronic liver disease. We assessed the use of the scoring system in children. METHODS Twenty-eight pediatric patients with AIH and/or sclerosing cholangitis were reviewed. Clinical, laboratory, and histologic data were collected to score patients both before and after standard treatment. RESULTS There were 8 boys and 20 girls. The median age at diagnosis was 11 years (range, 2-16 years). Twenty-one of 28 children were diagnosed with AIH, 4 as isolated primary sclerosing cholangitis (PSC), and 3 as overlap syndrome. At presentation, 18 of 21 (86%) with AIH scored as definite AIH and 3 of 21 (14%) scored as probable. No patient clinically diagnosed as AIH scored as other. Seven of 28 patients had proven PSC. All patients with isolated PSC scored as other. The 3 with overlap syndrome scored as definite AIH. When the gamma-glutamyltranspeptidase (GGT) ratio was substituted for the alkaline phosphatase (ALP) ratio, 5 patients were reclassified from definite to probable AIH. Four of these 5 had an incomplete response to therapy, and 2 of 4 have confirmed overlap syndrome. CONCLUSIONS The IAIHG scoring system has a use in children. Patients who fall into the other category should have cholangiographic imaging. Using the GGT ratio instead of the ALP ratio in the IAIHG score may improve the specificity for children, identifying those likely to have biliary disease. When GGT is used, patients classified as needing probable pretreatment should be considered for biliary imaging.

Biliary atresia and other cholestatic childhood diseases: Advances and future challenges.

Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10-19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research.

Biliary Atresia in Canada: The Effect of Centre Caseload Experience on Outcome

Objectives: Biliary atresia (BA) is a leading cause of end-stage paediatric liver disease. Standard BA treatment is sequential surgery with an initial Kasai procedure (KP) followed by liver transplant (LT) for patients who progress to liver failure. A key determinant for the post-KP patient survival with their native liver is patient age at KP (older age, poorer outcome). Recently, European studies have reported that caseload experience influences prognosis with centres managing <5 cases per year (UK) or <2 cases per year (France) having worse survival. Our study investigates the effect of caseload experience on outcomes of Canadian patients with BA. Patients and Methods: A national database of cases with BA, born from 1992 to 2002, was examined. Patients were grouped according to treatment centre size (A: on average <1 case per year; B: 1 to 3 cases per year; and C: >3 cases per year). Overall patient, post-KP native liver, and LT survivals were compared between centres. Outcome parameters were reevaluated for patients grouped by the largest Canadian centre (>5 cases per year) and all other centres (<5 cases per year). Results: Two-hundred thirty patients were identified among 6 group A, 4 group B, and 2 group C centres. The overall median age at KP was 64 days. There were no significant differences in patient, post-KP native liver, or LT survivals between the sized centres and even the largest centre, with the overall 4-year post-KP native liver survival being 39%. Conclusions: Caseload experience does not importantly affect the outcomes for Canadian children with BA. Although outcomes in Canada are comparable to those elsewhere, national policies directed towards timely referral and earlier age at KP rather than centralisation of care are needed.

Does Adjuvant Steroid Therapy Post-Kasai Portoenterostomy Improve the Outcome of Biliary Atresia? A Systematic Review and Meta-Analysis

BACKGROUND The role of adjuvant steroid therapy in the postoperative management of patients with biliary atresia (BA) is unclear. OBJECTIVE To systematically review the literature and perform a meta-analysis to determine the efficacy of adjuvant steroid therapy post-Kasai portoenterostomy (KP) on BA outcome. METHODS A systematic review and meta-analysis of randomized trials and⁄or observational studies that examined the role of steroids on BA outcomes published between January 1969 and June 2010 was conducted. Studies were identified using the Medline, PubMed, EMBASE and Cochrane databases. RESULTS Sixteen observational studies and one randomized controlled trial (RCT) were found. Four of the 16 observational studies (160 participants) and the RCT (73 participants) met the entry criteria and were eligible to be included in the analysis. There was no statistically significant difference in the effect of steroids either on normalizing serum bilirubin levels at six months (pooled OR 1.48 [95% CI 0.67 to 3.28]) or in delaying the need for early liver transplantation (within the first year post-KP (pooled OR 0.59 [95% CI 0.21 to 1.72]). CONCLUSION The present meta-analysis did not find a significant effect of steroid over standard therapy, either in normalizing serum bilirubin levels at six months or at delaying the need for early liver transplantation post-KP. RCT studies of sufficient size and comprehensive design using high-dose steroids are needed to determine the effectiveness of steroids on the short and intermediate post-KP outcomes for BA patients.

CLMP is required for intestinal development, and loss-of-function mutations cause congenital short-bowel syndrome

BACKGROUND & AIMS Short-bowel syndrome usually results from surgical resection of the small intestine for diseases such as intestinal atresias, volvulus, and necrotizing enterocolitis. Patients with congenital short-bowel syndrome (CSBS) are born with a substantial shortening of the small intestine, to a mean length of 50 cm, compared with a normal length at birth of 190-280 cm. They also are born with intestinal malrotation. Because CSBS occurs in many consanguineous families, it is considered to be an autosomal-recessive disorder. We aimed to identify and characterize the genetic factor causing CSBS. METHODS We performed homozygosity mapping using 610,000 K single-nucleotide polymorphism arrays to analyze the genomes of 5 patients with CSBS. After identifying a gene causing the disease, we determined its expression pattern in human embryos. We also overexpressed forms of the gene product that were and were not associated with CSBS in Chinese Hamster Ovary and T84 cells and generated a zebrafish model of the disease. RESULTS We identified loss-of-function mutations in Coxsackie- and adenovirus receptor-like membrane protein (CLMP) in CSBS patients. CLMP is a tight-junction-associated protein that is expressed in the intestine of human embryos throughout development. Mutations in CLMP prevented its normal localization to the cell membrane. Knock-down experiments in zebrafish resulted in general developmental defects, including shortening of the intestine and the absence of goblet cells. Because goblet cells are characteristic for the midintestine in zebrafish, which resembles the small intestine in human beings, the zebrafish model mimics CSBS. CONCLUSIONS Loss-of-function mutations in CLMP cause CSBS in human beings, likely by interfering with tight-junction formation, which disrupts intestinal development. Furthermore, we developed a zebrafish model of CSBS.

Congenital Short Bowel Syndrome: A Case Report and Review of the Literature

Congenital short bowel syndrome (SBS) is a rare condition of the newborn, with several reports demonstrating high mortality. A six-week-old boy presented with chronic diarrhea and failure to thrive. An upper gastrointestinal endoscopy showed a straight duodenum, and multiple small bowel biopsies were histologically normal. An upper gastrointestinal series showed malrotation. At laparotomy, the small bowel was 50 cm in length, confirming the diagnosis of congenital SBS. Parenteral nutrition was initiated and enteral feeding with an amino acid-based formula containing long-chain fatty acids was introduced early and gradually advanced. At the last follow-up examination at 24 months, he was thriving on a regular diet, with normal growth and development. Long-term survival of children with congenital SBS is now possible if enteral feeds are introduced early to promote intestinal adaptation, with subsequent weaning off parenteral nutrition.

Biliary atresia with associated structural malformations in Canadian infants

Background: Biliary atresia (BA) is associated with extrahepatic congenital malformations in a minority of affected infants. The term commonly applied to this subgroup is ‘BASM’ for biliary atresia splenic malformation syndrome, as spleen abnormalities are prominent.

Home-based screening for biliary atresia using infant stool colour cards: A large-scale prospective cohort study and cost-effectiveness analysis

Objective Biliary atresia (BA), a leading cause of paediatric liver failure and liver transplantation, manifests by three weeks of life as jaundice with acholic stools. Poor outcomes due to delayed diagnosis remain a problem worldwide. We evaluated and assessed the cost-effectiveness of methods of introducing a BA Infant Stool Colour Card (ISCC) screening programme in Canada. Setting and Methods A prospective study at BC Women’s Hospital recruited consecutive healthy newborns through six incrementally more intensive screening approaches. Under the baseline “passive” strategy, families received ISCCs at maternity, with instructions to monitor infant stool colour daily and return the ISCC by mail at age 30 days. Additional strategies were: ISCC mailed to family physician; reminder letters or telephone calls to families or physicians. Random telephone surveys of ISCC non-returners assessed total card utilization. Primary outcome was ISCC utilization rate expressed as a composite outcome of the ISCC return rate and non-returned ISCC use. Markov modelling was used to predict incremental costs and life years gained from screening (passive and reminder), compared with no screening, over a 10-year time horizon. Results 6,187 families were enrolled. Card utilization rates in the passive screening strategy were estimated at 60–94%. For a Canadian population, the increase in cost for passive screening, compared with no screening, is