published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Liver transplantation (LT) is the most effective treatment for hepatitis B virus (HBV) related liver failure and hepatocellular carcinoma (HCC). Nevertheless, HBV and HCC recurrence rate remains high after LT. Previous studies have shown that HBV reactivation is associated with HCC recurrence and poor prognosis after LT. The main objectives of this study are to investigate the risk factors for HBV and HCC recurrence after LT, the efficacy of antiviral drugs to prevent HBV reactivation and the underlying mechanisms contributing to HBV reactivation. Firstly, we investigate the risk factor for HBV and HCC recurrence in 551 HBsAg seropositive LT patients, of whom374 had no tumor and 177 had HCC. All patients received indefinite antiviral treatment after LT. The study showed that pre-LT HBV DNA levels and HCC recurrence were significantly associated with HBV reactivation after LT. Younger age, lower Child-Pugh score, beyond UCSF criteria, higher AST level, salvage LT, older donor, HBsAg seropositive at the last follow-up and HBV reactivation after LT were independent risk factors for HCC recurrence. HCC recurrence alone accounts for poor overall survival. The sequence analysis identified drug-resistant mutants as the main contributors to HBV reactivation. In addition, wild-type (antiviral drug-sensitive) HBV reactivation was identified in patients with HCC recurrence. Secondly, we investigate the efficacy of antiviral drugs monotherapy (Lamivudine or Entecavir) in preventing HBV reactivation. This study showed that patients receiving lamivudine (LAM) experienced significantly greater HBV reactivation and HCC recurrence than those receiving entecavir (ETV). In patients with no tumors, HBV reactivation was found in the LAM groups but not in the ETV groups, due to the appearance of a LAM drug-resistant mutant. In patients with HCC recurrence, HBV reactivation was found in both treatment groups. Wild-type HBV reactivation was identified in 17% (5/29) and 100% (1/1) of HCC patients receiving LAM and ETV respectively. This suggests that, although ETV had higher genetic barriers to HBV drug resistance; it still cannot prevent wild-type HBV reactivation in HCC-recurrent patients. Thirdly, we investigate the expression of HBV markers in HCC and adjacent non-tumor tissues. Origin of circulating HBV was identified using genetic distance analysis of HBV isolated from different compartments (i.e. HCC and adjacent non-tumor tissues). The study showed that, in some HCC cases, the expressions of HBsAg and HBV replicative efficiency are higher in HCC tissues than in adjacent non-tumor tissues. Moreover, through genetic distance analysis, we demonstrated that HBV reactivation could originate from recurrent HCC. These data suggest that HCC supports HBV replication and that HBV is secreted from recurrent HCC. Finally, we demonstrate that the up-regulation of drug-specific ABC-transporters is significantly associated with patients with HCC recurrence. In vitro studies also showed that the up-regulation of ABCG2 contributes to antiviral drug-resistant. Finally, we demonstrate that the up-regulation of drug-specific ABC-transporters is significantly associated with patients with HCC recurrence. In vitro studies also showed that the up-regulation of ABCG2 contributes to antiviral drug-resistant. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Die Lebertransplantation ist ein etabliertes Therapieverfahren bei akuten sowie chronischen Leberversagen. Aufgrund des stetig steigenden Bedarfs an Transplantationsorganen stellt die Verteilung der Spenderorgane eine immense Herausforderung dar. Im Jahr 2006 wurde ein neues Allokationssystem eingeführt, welches objektiv anhand vorliegender Labordaten die Dringlichkeit einer Organtransplantation einschätzt. Die hier vorliegende Dissertation zeigt die Auswirkungen des neuen Allokationssystems auf die Ergebnisse nach einer Lebertransplantation am Universitätsklinikum Leipzig. Die Einführung des neuen Allokationssystems führte zu einer Verkürzung der Wartezeit auf der Transplantationsliste und zu einer niedrigeren Wartelistenmortalität. Dem gegenüber stehen erhöhte postoperative Komplikationsraten sowie Kosten. Um die limitiert verfügbaren Spenderorgane mit größtmöglicher Erfolgsaussicht transplantieren zu können, sind prädiktive Modelle zur Abschätzung des outcomes nach Lebertransplantation etabliert worden. In dem betrachteten Patientenkollektiv am Universitätsklinikum Leipzig konnten sowohl der SALT-Wert als auch die präoperative intensivmedizinische Trias als Prognosefaktoren für das Überleben nach Lebertransplantation beschrieben werden. In Zukunft wird die Anwendung eines Prognosefaktors bereits im Organallokationsprozess eine immer größere Rolle einnehmen um im ethischen Problemfeld aus Organknappheit und erhöhtem Organbedarf den gesellschaftlichen Ansprüchen gerecht zu werden.

Background: Liver transplantation is a curative method for end-stage liver diseases, small unresectable hepatocellular carcinoma and acute liver failure. The discovery of immunosuppressive drugs increases the survival rate of liver transplanted recipients by reducing the incidence of graft rejection. Several complications such as renal dysfunction and increase risk of malignancy result from life-long treatment of transplanted recipients with immunosuppressant. If recipients are over-immunosuppressed, the risk of infection might be increased. On the other hands, if recipients are under-immunosuppressed, the risk of rejection would be increased. It should be useful if a test or a bio-marker that could predict and differentiate infection and rejection in transplanted recipients. Therefore, patients could be treated before adverse conditions. Although therapeutic drug monitoring has been performed as a routine test, it is mainly targeted for minimizing drug toxicity but little help in predicting infection and rejection. A new assay named Cylex? Immuknow? assay is designed to measure global cell mediated immunity of immunosuppressed population, by quantifying the amount of ATP synthesis by CD4+ T cells in response to PHA stimulation. It is undergoing evaluation in assessing the immune status of patients in order to predict the risk of infection and rejection, and also other conditions. (1, 2) Objectives: In this pilot study, we would like to evaluate ImmuKnow for predicting the risk of infection and rejection in liver transplanted recipients in Hong Kong. Methods: Blood samples were collected from liver transplanted recipients at different time intervals. The immune cell response of these patients was measured by Immuknow assay. Patients with low immune response might have a high risk of infection, patients with high immune response might have a high risk of rejection, and patients with moderate immune response should be clinically stable. Results and conclusion: Twenty-six blood samples were collected from eight transplanted recipients. The average Immuknow assay value for the post-transplant samples was 304.6 ng/mL ATP which represented moderate immune cell response according to the interpretation table. (Table 3) This was reasonable as the subjects were all clinically stable by well-controlled immunosuppression. The result was consistent with other studies. (1, 3) However, the association between low immune cell response and infection, and the association between high immune cell response and graft rejection could not be investigated as both of these conditions were not found in this pilot study. A larger study including episodes of infection and rejection should be conducted in order to evaluate the value of Immuknow assay more completely. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Thesis (M.Sc.). / Written for the Dept. of Epidemiology and Biostatistics. Title from title page of PDF (viewed 2008/05/14). Includes bibliographical references.

Thesis (doctoral)--Lund University, 1992. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1992. / Added t.p. with thesis statement inserted.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior

Orthotopic liver transplantation is the treatment of choice for many patients with end-stage liver disease. Despite advances in immunosuppression, acute rejection remains common (up to 70%) and results in significant patient morbidity. It is frequently difficult to distinguish abnormal liver function due to rejection from that due to infection, biliary obstruction or ischaemic injury without performing invasive procedures such as a liver biopsy or angiography which may be Clinically, the diagnosis of rejection is usually once the immunological process is already hazardous. made late, established. In this study, we evaluated standard biochemical parameters and cytokine concentrations (IL-1, IL-6 and TNF-alpha) in serial samples of bile obtained post-operatively via the Ttubes of patients following orthotopic liver transplantation in order to determine whether there are any biochemical or immunological pointers to the early diagnosis of rejection which would enable earlier administration of appropriate antirejection therapy. Biliary cytokines did not prove to be useful and reliable markers of early rejection. Serial measurement of biliary bilirubin levels showed an early and significant decrease a few days prior to rejection, and were a more sensitive marker of graft function than serum bilirubin levels.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24530号 / 医博第4972号 / 新制||医||1065(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小濱 和貴, 教授 小林 恭, 教授 川口 義弥 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM