No description available.

Thesis (M. Phil.)--University of Hong Kong, 2010. / Includes bibliographical references (p. 167-183). Also available in print.

Biliary atresia (BA) is a rare and severe cholestatic disease in neonates characterized by an idiopathic inflammatory process affecting both intra- and extra-hepatic bile ducts, causing cholestasis and ultimately leading to obliteration of the biliary tract. Through a previous genome-wide-association-study (GWAS) on Han Chinese, we discovered association of the 10q24.2 region encompassing ADD3 and XPNPEP1 gene. But disease pathogenesis and genetic architecture of BA is still obscure. We mapped the 10q24.2 association locus with 107 single nucleotide polymorphisms (SNPs) on 339 Han Chinese patients and 401 matched controls, follow-up studies of the association signals were performed. We revealed the common risk haplotype encompassing 5 tagging-SNPs, capturing the risk-predisposing alleles in 10q24.2 [logistic regression p=5.32x10-11; odds ratio, OR:2.38; confidence interval, CI:(2.14-2.62)]. No deleterious rare variants (RVs) residing on the risk haplotype were found, dismissing the theory of “synthetic” association. Moreover, the BA-associated potential regulatory SNPs correlated ADD3 gene expression (linear regression p=0.0030). Remarkably, the risk haplotype frequency coincides with BA incidences in the general population, and, positive selection (favoring the derived alleles that arose from mutations) was evident at the ADD3 locus. Our finding suggested the complexity of BA genetic architecture and role of environmental effects in the disease. We then revisited BA GWAS dataset and annotated the association signals with expression quantitative trail loci (eQTL) information available on normal adult livers. We did not see excessive enrichment of BA associated SNPs in liver eQTLs. We speculate that the liver eQTLs currently available relate to adulthood liver function and are not necessarily involved in liver development, adaptation to oxidative stress, or inflammation changes seen in BA pathophysiology. To investigate whether rare alleles can predispose to BA, we called copy number variations (CNVs) from the GWAS Affymetrix gene chip 5.0. We obtained 86 BA private CNVs distributed among 131 BA patients were compared to the CNV profile of 11,943 database samples and 846 hypertension disease samples. Assuming that pathogenic CNVs interrupt dosage-sensitive genes, we prioritized the dosage-sensitive genes and the pathogenic CNVs by integrating multiple lines of evidence. Through gene set enrichment analysis we found that the ‘core’ genes affected by BA CNVs were members of the Calcium signaling pathway, which has been involved in the pathogenesis of polycystic liver and kidney diseases. Further we initiated the survey on rare coding variants in BA through Exome sequencing 23 BA liver genomes, while patients’ blood DNA and parental DNA would be examined in the validation stage to validate de novo mutations, including somatic mosaicism in liver. We found inherited deleterious mutations in polycystic liver and kidney disease genes in BA patients, and the role of these mutations in BA pathogenesis is being investigated. Functional validation of the BA variants identified in this study is compulsory given the overall obscurity of BA pathogenesis. Together, this study presents a comprehensive catalog of both common and rare variants implicated in BA. We hope that our findings will contribute to enriching the BA-associated genetic network. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Malignant obstructive jaundice is always encountered in advanced stage. Malignancies include Distal Bile duct Carcinoma, Ampulla of Vater Carcinoma, and Pancreas Carcinoma are sometimes impossible to cure and resect. Therefore, palliative treatments are the only way to relieve the disease for the patients to have a better quality of life in their remaining life- span. Available palliative treatments include stenting and surgical bypass. In our analysis, metallic stenting and double bypass composing hepaticojejunostomy and gastrojejunostomy are studied as they can be considered as the two most efficient palliative methods so far that are widely used in Hong Kong in the management of malignant biliary obstruction. The treatment options depends on both the physicians and the patient. However, patients are often on the horns of a dilemma when they are allowed to choose these palliative treatments. This study hence aim to compare the cost-effectiveness of metallic stenting and surgical double bypass palliative treatment among five factors: 1) Number of hospital stay, 2) Re-admission rate, 3) Overall complication, 4) Change of bilirubin level and 5) Survival rate. A total of 40 patients data are being retrieved from the Queen Mary Hospital as 20 data are form the metallic stenting group, while the other 20 data are from surgical bypass. After collecting the data and finishing the study, it was found that apart from a longer hospital stay, the surgical bypass patient group would generally have a lower re-admission and complication rate. While the parameters include bilirubin change before and after the treatment and the survival rate are not significantly different, which indicated these two parameters may not be the determining factors when deciding the treatment choice. Based on the research outcome, surgical bypass may be a better choice of palliative treatment in the management of Malignant Biliary Obstruction that allows patients to obtain a better quality of life. / published_or_final_version / Medicine / Master / Master of Medical Sciences

Thesis (doctoral)--Ludwig Maximilians-Universität zu München, 1979.

A research report submitted to the degree of Master of Medicine in the Department of Surgery for the University of the Witwatersrand Health Sciences, 2013 / Biliary atresia (BA) is characterised by a progressive obliterative cholangiopathy. If surgical treatment by a Kasai Portoenterostomy (KP) is undertaken early on in life there is the potential for successful bile drainage. The natural disease progression without intervention results in fibrosis and cirrhosis, necessitating liver transplantation before two years of life. Despite the advances in the management of biliary atresia over the recent decades we still do not have a good indicator of which patients will do well after surgery and which will require further intervention for their liver dysfunction. There are many clinical and serological indicators that suggest liver failure, but liver histology remains the gold standard indicating the extent of liver damage. This is, however, being slowly replaced by various new less-invasive biological markers, including the Aminotransferase Aspartate to Platelet Ratio Index (APRi). This study looks at this biological marker for patients with biliary atresia with reference to their level of disease at the time of surgery and whether it is a prognostic tool for long-term outcomes in this group of patients.

Senescence is a highly efficient mechanism that provides an irreversible barrier to cell cycle progression to prevent undesired proliferation. However, under pathological circumstances, senescence can adversely affect organ function, viability and regeneration. In the context of biliary disease, we hypothesize that senescence is initiated in the bile ducts and spreads to the liver parenchyma, impairing the liver’s regenerative capacity and aggravating the condition. We have developed a mouse model of biliary senescence, based on the conditional deletion of Mdm2 in bile ducts, that mimics clinical features of biliary disease. Using this model, we studied the underlying mechanisms that characterize biliary disease, and established an essential role of TGFβ in paracrine senescence-associated regeneration. Lastly, we disrupted TGFβ signalling to therapeutically rescue this phenotype in our model of biliary senescence. These results reveal the detrimental role of senescence in biliary disease, and a TGFβ- dependent mechanism for dissemination of senescence from the biliary epithelium to the parenchyma, impairing liver function. Finally, we have identified TGFβ signalling disruption as a potential therapeutic target to limit senescence-dependent aggravation in human cholangiopathies.

Graduation date: 1991

Background and Purpose: Percutaneous transhepatic biliary drainage remains a painful procedure in many cases despite the routine use of large amounts of intravenous sedation. We present a feasibility study of thoracic paravertebral blocks in an effort to reduce pain during and following the procedure and reduce requirements for intravenous sedation. Methods: Ten consecutive patients undergoing biliary drainage procedures received fluoroscopically guided paravertebral blocks and then had supplemental intravenous sedation as required to maintain patient comfort. Levels T8-T9 and T9-T10 on the right were targeted with 10-20 ml of 0.5% bupivacaine. Sedation requirements and pain levels were recorded. Results: Ten biliary drainage procedures in 8 patients were performed for malignancy in 8 cases and for stones in 2. The mean midazolam use was 1.13 mg IV, and the mean fentanyl requirement was 60.0 μg IV in the block patients. Two episodes of hypotension, which responded promptly to volume replacement, may have been related to the block. No serious complications were encountered. The mean pain score when traversing the chest wall, liver capsule, and upon entering the bile ducts was 0.1 on a scale of 0 to 10, with 1 patient reporting a pain level of 1 and 9 reporting 0. The mean peak pain score, encountered when manipulating at the common bile duct level or when addressing stones there, was 5.4 and ranged from 0 to 10. Conclusions: Thoracic paravertebral block with intravenous sedation supplementation appears to be a feasible method of pain control during biliary interventions.

No description available.