Are all patients with short segment Hirschsprung's disease equal? A retrospective multicenter study.

BACKGROUND/PURPOSE: Short segment Hirschsprung's disease (HSCR) carries a better prognosis than long segment disease, but the definition of short is controversial. The objective of this study is to determine anatomically the extent of disease involvement that would be associated with a better functional outcome. METHODS: This is a retrospective multicenter (n = 3) study with patients (≥ 3 years) who had transanal pullthrough operation done for aganglionosis limited to the recto-sigmoid colon were reviewed. The extent of disease involvement and bowel resection was retrieved by reviewing the operative records as well as histopathological reports of the resected specimens. Clinical assessment was performed according to the criteria of a seven-itemed bowel function score (BFS) (maximum score = 20). Manometric assessment was performed with anorectal manometry. RESULTS: The study period started from 2003 to 45 patients were studied with median age at assessment = 52.0 months and operation = 3.0 months. The disease involvement was categorized into upper sigmoid-descending colon (DC) (n = 8), sigmoid colon (SC) (n = 12), upper rectum (UR) (n = 14) and lower rectum (LR) (n = 11) according to the level of normal biopsy result. There was no significant difference in the age of assessment between the four groups. The median BFSs in the DC, SC, UR and LR were 13, 15, 17 and 17, respectively (p = 0.01). Nine patients from the DC and SC groups reported soiling for more than twice per week. Sub-group analysis comparing patients with and without the entire sigmoid colon resected revealed worse functional outcomes in terms of the incidence of soiling (40.7 vs 22.2%, p = 0.05) and the BFS (14 vs 18, p = 0.04) in the former group. Anorectal manometry did not reveal any significant difference between the four groups, but a higher proportion of patients in the UR and LR groups appeared to have a normal sphincter resting pressure (DC vs SC vs UR vs LR = 62.5 vs 75.0 vs 85.7 vs 80.0%, p = 0.10). CONCLUSION: Patients with short segment HSCR are not equal at all. HSCR patients with aganglionosis limited to the rectum without the need of removing the entire sigmoid colon have a better bowel control and overall functional score. Less bowel loss and colonic dissection maybe the underlying reasons. Although future studies with a larger sample size and a longer follow-up period are required to validate the results of this study, it has provided a new insight to the current understanding of short segment disease in HSCR.

Common genetic variants regulating ADD3 gene expression alter biliary atresia risk.

BACKGROUND & AIMS: Biliary atresia (BA) is a rare and most severe cholestatic disease in neonates, but the pathogenic mechanisms are unknown. Through a previous genome wide association study (GWAS) on Han Chinese, we discovered association of the 10q24.2 region encompassing ADD3 and XPNPEP1 genes, which was replicated in Chinese and Thai populations. This study aims to fully characterize the genetic architecture at 10q24.2 and to reveal the link between the genetic variants and BA. METHODS: We genotyped 107 single nucleotide polymorphisms (SNPs) in 10q24.2 in 339 Han Chinese patients and 401 matched controls using Sequenom. Exhaustive follow-up studies of the association signals were performed. RESULTS: The combined BA-association p-value of the GWAS SNP (rs17095355) achieved 6.06×10(-10). Further, we revealed the common risk haplotype encompassing 5 tagging-SNPs, capturing the risk-predisposing alleles in 10q24.2 [p=5.32×10(-11); odds ratio, OR: 2.38; confidence interval, CI: (2.14-2.62)]. Through Sanger sequencing, no deleterious rare variants (RVs) residing in the risk haplotype were found, dismissing the theory of "synthetic" association. Moreover, in bioinformatics and in vivo genotype-expression investigations, the BA-associated potentially regulatory SNPs correlated with ADD3 gene expression (n=36; p=0.0030). Remarkably, the risk haplotype frequency coincides with BA incidences in the population, and, positive selection (favoring the derived alleles that arose from mutations) was evident at the ADD3 locus, suggesting a possible role for the BA-associated common variants in shaping the general population diversity. CONCLUSIONS: Common genetic variants in 10q24.2 can alter BA risk by regulating ADD3 expression levels in the liver, and may exert an effect on disease epidemiology and on the general population.

Life long follow up and management strategies of patients living with native livers after Kasai portoenterostomy.

We present a 37 years' experience in the management of biliary atresia (BA) and discuss long-term complications after Kasai portoenterostomy (KPE). A retrospective territory-wide study from 1980 to 2017 on 231 patients with open KPE from three tertiary paediatric surgical centres was performed. Outcome parameters were clearance of jaundice (COJ), native liver survival (NLS) and long-term complications. Factors affecting the operative outcomes were analyzed. The median duration of follow up was 17.5 (IQR: 13.5-22) years. Over 66% of patients became jaundice-freed at 1 year after KPE. Seventy patients (30.3%) received liver transplant (LT) at a median age of 6.2 (IQR: 4.3-8.4) years. The NLS rates at 10 and 20 years were 70.7% and 61.5% respectively with no significant change over the study period. The median age at KPE was 59 (IQR: 49-67) days. KPE performed before 70 days was associated with higher odd ratios for successful drainage but the age of KPE did not have an impact on the long-term NLS. Among all native liver survivors (n = 153), the median bilirubin level was 24 (IQR: 16-36) µmol/L. Portal hypertension (PHT) and recurrent cholangitis were found in 51.6% and 27.5% of them respectively. With a vigilant follow up program, more than 60% of BA patients could remain stable with the disease and achieve long-term survival without LT. Although cholestasis, portal hypertension and recurrent cholangitis are common in long-term NLS, with a comprehensive follow management strategy, they do not always necessitate LT. Our study serves as an example for countries where deceased donor organs are scarce due to very low donation rate.

Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis.

BACKGROUND: Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. We aim to explore the BA phenotypic features and to delineate the source of its variance. METHODS: The study is a cross-sectional observational study collating with case/control association analysis. One-hundred-and-eighty-one type III non-syndromic BA patients and 431 controls were included for case-control association tests, including 89 patients (47.19% males, born June 15th, 1981 to September 17th, 2007) have detailed clinical records with follow-up of the disease course (median ~17.2 years). BA-association genes from the genome-wide gene-based association test on common genetic variants (CV) and rare copy-number-variants (CNVs) from the genome-wide survey, the later comprise only CNVs > 100 kb and found in the BA patients but not in the local population (N = 1,381) or the database (N = 11,943). Hereby comorbidity is defined as a chronic disease that affects the BA patients but has no known relationship with BA or with the BA treatment. We examined genotype-phenotype correlations of CNVs, connectivity of these novel variants with BA-associated CVs, and their role in the BA candidate gene network. RESULTS: Of the 89 patients, 41.57% have comorbidities, including autoimmune-allergic disorders (22.47%). They carried 29 BA-private CNVs, including 3 CNVs underpinning the carriers' immunity comorbidity and one JAG1 micro-deletion. The BA-CNV-intersected genes (N = 102) and the CV-tagged genes (N = 103) were both enriched with immune-inflammatory pathway genes (FDR q < 0.20), and the two gene sets were interconnected (permutation p = 0.039). The molecular network representing CVs and rare-CNV association genes fit into a core/periphery structure, the immune genes and their related modules are found at the coherence core of all connections, suggesting its dominant role in the BA pathogenesis pathway. CONCLUSIONS: The study highlights a patient-complexity phenomenon as a novel BA phenotypic feature, which is underpinned by rare-CNVs that biologically converge with CVs into the immune-inflammatory pathway and drives the BA occurrence and the likely BA association with immune diseases in clinics.

What is the role of laparoscopic surgery in intussusception?

BACKGROUND: Assessing the role of laparoscopy in the management of intussusception. METHODS: A retrospective review of children aged up to 17 years who had surgery for intussusception at this institution between 1 January 2004 and 31 December 2013. RESULTS: The cohort of 44 individuals (18 females) presented at a median age of 9 months (range 2.5 months-15.75 years) with intussusception; 36 patients had undergone a failed pneumatic reduction. Thirty-seven patients had an initial laparoscopic approach. Conversion was required in 13 individuals: inability to reduce a 'tight' intussusception in seven individuals, limited working space in four individuals, and inadequate tactile response in two individuals. Twenty-four patients (54%) had the laparoscopic approach completed. An open approach was chosen for seven individuals at a median age of 5 (range 4-11) months: three individuals had marked abdominal distension, two individuals had a pneumoperitoneum and two individuals presented with a large central mass. Together with the 13 conversions, a total of 20 patients (46%) underwent an open approach. The more distal the apex of the intussusception, the more likely open surgery was. Hospital stays for the subgroup of patients with successfully completed laparoscopic intervention (n = 24) were shorter than for the open surgery group (n = 20) with P = 0.0145, but the open procedure was used to manage the more challenging cases. The subgroup of seven infants undergoing direct open surgery were significantly younger than the remaining individuals (P = 0.0046). CONCLUSION: Laparoscopic intervention is meaningful in approximately 50% of children requiring a surgical reduction.