臺灣博碩士論文加值系統

肝臟移植是終末期肝病和急性肝衰竭患者的唯一救命治療。在亞洲，活體肝移植已被廣泛接受，且受贈者存活率接近90％。然而，活體肝移植術後最初的不良功能（early allograft dysfunction（EAD））發生率約為25％，與移植後的排斥或死亡有關。術後發生EAD的患者在90天內的移植失敗風險是沒有發生EAD的患者的5.2倍。造成EAD的因素包含捐贈者（如脂肪肝的嚴重度），受贈者（如肝腫瘤與需要血液透析），及手術因子等，進而影響受贈者的存活率。在臨床上，EAD的診斷是在術後一周內若符合至少一項標準(血清轉氨酶值，總膽紅素上升或國際標準化比率上升)。但由於肝臟是一個負責小分子和複雜分子的合成和分解代謝的多功能器官，科學家有機會可利用代謝體學更進一步的研究，找尋新的生物標記以預測肝臟移植後移植物及受贈者的存活率。因此，我們希望能夠從不同受贈者族群及其相對應的捐贈者中找出新的生物標誌物，更準確評估肝臟移植後的肝臟功能，並及早介入治療。另外在臨床上，肝臟移植手術中受贈者之血液動力不平穩也會影響其術後成果。準確的血液動力測量需要置放侵入性肺動脈導管，但此程序可能會造成氣胸，空氣栓塞，導管打結，甚至於右心或肺動脈破裂。
在此研究中，將於基礎與臨床上個別探討接受肝臟移植的病患在術中血液動力學的監控及術後的肝臟功能變化。主要成果包含：
(一) 探討肝臟移植中，使用非侵入性監測儀器之適當性
(二) 以健保資料庫之大數據，探討肝臟移植後腫瘤及心血管疾病之發生率。
(三) 利用代謝體學探討受贈者及其術後肝功能的相聯性。
(四) 利用以代謝體學找尋之生物標記物其對死亡率與住院長短之預測。

Liver transplantation is a life-saving treatment for patients with end-stage liver disease and acute liver failure. Living donor liver transplantation (LDLT) has been widely accepted with a survival rate close to 90%. However, early allograft dysfunction (EAD) after LDLT is associated with cellular rejection or mortality. Patients who develop EAD have a 5.2-fold higher risk of graft failure within 90 days compared to patients who do not develop EAD. Clinically, the diagnosis of EAD is clinically based on the levels of serum transaminases, total bilirubin and the international normalized ratio within the first postoperative week. The development of EAD is multifactorial. Since the liver is a multi-functional organ responsible for the synthesis and catabolism of small and complex molecules, metabolomics has given scientists an opportunity to closely examine metabolites that may help to predict graft viability and function and even patient survival after liver transplantation. Researchers hope to find new biomarkers to more accurately assess liver function in association with EAD after LDLT. In addition, clinically, intraoperative hemodynamic instability may affect postoperative outcomes. To maintain hemodynamic stability, an accurate monitoring system is necessary before treatment can be provided. The gold standard for accurate hemodynamic measurements is the use of pulmonary artery catheter (PAC), which is invasive and can cause complications such as pneumothorax, air embolism, catheter knotting, and even rupture of the right heart or pulmonary artery. In this study, intraoperative hemodynamic monitoring and postoperative liver function will be discussed in the clinical and basic aspects of patients undergoing LDLT. The main results include:
(i) Discussing the interchangeability and trending ability of noninvasive cardiac output monitors
(ii) Using National Database to discuss the incidences of de novo cancer and cardiovascular disease after liver transplantation
(iii) Using metabolomics to identify the association of recipients and their postoperative liver function
(iv) Exploring the connection between biomarkers and graft/recipient survival and the length of hospital stay

指導教授推薦書……………………………………………………
口試委員審定書……………………………………………………
誌謝………………………………………………………………… iii
中文摘要……………………………………………………………. v
ABSTRACT………………………………………………………… vii
ABBREVIATION………………………………………………….. ix
Chapter 1 Introduction on Liver Transplantation......................... 1
1.1 Types of Liver Transplantation……………………………... 2
1.1.1 De Novo Malignancies after Liver Transplantation from Taiwan’s Database……………………………. 4
1.1.2 Cardiovascular Disease Risks after Liver Transplantation from Taiwan’s Database……………. 7
1.2 Selection Criteria on Recipient……………………………... 10
1.3 Selection Criteria on Living Donor………………………… 12
1.4 Intraoperative Monitoring and Management……………….. 14
1.4.1 Arterial Waveform Monitoring –FloTrac…………… 16
1.4.2 Electrical Velocimetry Monitoring System - Aesculon™………………………………………….. 18
1.5 Primary Graft Dysfunction…………………………………. 24
Chapter 2 Introduction to Instrumentation in Metabolomic Analysis…………………………………………………………….. 27
2.1 Metabolomics……………………………………………….. 27
2.2 Nuclear Magnetic Resonance Spectroscopy……………………………………………………. 29
2.3 Mass Spectrometry…………………………………………. 31
2.4 Data Analysis……………………………………………….. 34
Chapter 3 A Lipidomic Study of Early Allograft Dysfunction In Living Donor Liver Transplantation……………………………... 38
3.1 Methods and Materials……………………………………… 40
3.1.1 Patient Selection……………………………………… 40
3.1.2 Blood Samples……………………………………….. 41
3.1.3 NMR analysis of the plasma…………………………. 41
3.1.4 Liquid Chromatography coupled with Mass Spectrometry based Lipidomic…………………………….. 43
3.1.5 Ultra-performance liquid chromatography (UPLC)-based amino acid measurement…………………... 45
3.1.6 Statistical analysis……………………………………. 46
3.2 Results………………………………………………………. 47
3.2.1 Demographics and Clinical Data…………………….. 47
3.2.2 Change in circulatory amino acid profiles in recipients with EAD……………………………………….. 48
3.2.3 Changes in NMR plasma profiles in recipients with EAD………………………………………………………… 48
3.2.4 Changes in circulatory lipid profiles in recipients with EAD………………………………………………………… 49
3.2.5 Discriminative ability of potential biomarkers for EAD and in-hospital mortality…………………………… 49
3.2.6 External validation of lipidomic profiling as prediction of EAD, long hospital stay and in-hospital mortality……………………………………………………. 50
3.3 Discussion……….………………………………………….. 51
3.3.1 Amino Acid………………………………………...… 51
3.3.2 Lipids…………………………………………………. 52
3.3.3 Bilirubin……………………………………………… 55
Chapter 4 Conclusion........................................................................ 56
Chapter 5 Future Perspectives…………………………………... 59
Chapter 6 Figures…………………………………………………. 60
Figure 1. Flowchart of organ transplant recipients during 1996-201.. 60
Figure 2. Flowchart of organ transplant patients during 1996-2011... 61
Figure 3. Cumulative probability of any kind of vascular disease
from years after organ transplant…………………………………….
62
Figure 4. Cumulative probability of cardiovascular disease from
years after organ transplant…………………………………………..
63
Figure 5 Cumulative probability of cerebrovascular disease from
years after organ transplant…………………………………………..
64
Figure 6. Cumulative probability of peripheral vascular disease from
years after organ transplant…………………………………………..
65
Figure 7. Cumulative probability of deep vein thrombosis from
years after organ transplant………………………………………….
66
Figure 8. Modified formula of cardiac output analyses for the
FloTrac algorithm…………………………………………………… 67
Figure 9. Bland-Altman plot for COEv and COPAC………………… 68
Figure 10. Four-quadrant plot for comparing changes in COEv and
COPAC……………………………………………………………….
69
Figure 11. Schematic of the electrospray ionization process………... 70
Figure 12. Flow diagram of the patient selection, allocation and
analysis……………………………………………………………… 71
Figure 13. 1H NMR plasma profile model………………………….. 72
Figure 14. 1H NMR plasma profile model………………………….. 73
Figure 15. Plasma samples analyzed by LC-MS in electrospray
positive ion mode, comparing EAD and nonEAD recipients in
OPLS-DA plot……………………………………………………… 74
Figure 16. Plasma samples analyzed by LC-MS in electrospray
positive ion mode, comparing EAD and nonEAD recipients in 75
S-plot…………………………………………………………………
Figure 17. Plasma samples analyzed by LC-MS in electrospray
positive ion mode, comparing EAD and nonEAD recipients by class
permutation analysis………………………………………………… 76
Figure 18. Prediction of early allograft dysfunction in study cohort... 77
Figure 19. Prediction of long hospital stay in study cohort…………. 78
Figure 20. Prediction of all-cause in-hospital mortality in study
cohort…………………………………………………………….......
79
Figure 21. Prediction of early allograft dysfunction in validation
cohort………………………………………………………………...
80
Figure 22. Prediction of long hospital stay in validation cohort…….. 81
Figure 23. Prediction of all-cause in-hospital mortality in validation
cohort ………………………………………………………………..
82
Figure 24. Schematic illustration of metabolic disturbances
associated with poor outcomes of liver transplants………………… 83
Chapter 7 Tables………………………..………………………….. 84
Table 1. Risk of malignancies in liver tranplant recipients………….. 84
Table 2. Risk of vascular disease in liver transplant recipients……... 86
Table 3. Summary of clinical data for living donor liver
transplantation recipients……………………………………………. 87
Table 4. Biochemical data for the patients before and after liver
transplantation……………………………………………………….
88
Table 5. Concentrations of amino acids at T6 in study group………. 90
Table 6. A List of metabolites that discriminated the EAD from the
non-EAD groups …………………………………………………….
91
Table 7. Receiver operating characteristic (ROC) curve analysis for
individual metabolites in study and validation group……………….
93
Table 8. Demographic details from the validation population……… 94
Table 9. Biochemical details from the validation study population… 95
Chapter 8 References…….………………………………………... 96
Appendix……………………………………………………………. 112


List of Figures
Figure 1. Flowchart of organ transplant recipients during 1996-201.. 60
Figure 2. Flowchart of organ transplant patients during 1996-2011... 61
Figure 3. Cumulative probability of any kind of vascular disease
from years after organ transplant…………………………………….
62
Figure 4. Cumulative probability of cardiovascular disease from
years after organ transplant…………………………………………..
63
Figure 5 Cumulative probability of cerebrovascular disease from
years after organ transplant…………………………………………..
64
Figure 6. Cumulative probability of peripheral vascular disease from
years after organ transplant…………………………………………..
65
Figure 7. Cumulative probability of deep vein thrombosis from
years after organ transplant………………………………………….
66
Figure 8. Modified formula of cardiac output analyses for the
FloTrac algorithm…………………………………………………… 67
Figure 9. Bland-Altman plot for COEv and COPAC………………… 68
Figure 10. Four-quadrant plot for comparing changes in COEv and
COPAC……………………………………………………………….
69
Figure 11. Schematic of the electrospray ionization process………... 70
Figure 12. Flow diagram of the patient selection, allocation and
analysis……………………………………………………………… 71
Figure 13. 1H NMR plasma profile model………………………….. 72
Figure 14. 1H NMR plasma profile model………………………….. 73
Figure 15. Plasma samples analyzed by LC-MS in electrospray
positive ion mode, comparing EAD and nonEAD recipients in
OPLS-DA plot……………………………………………………… 74
Figure 16. Plasma samples analyzed by LC-MS in electrospray
positive ion mode, comparing EAD and nonEAD recipients in
S-plot………………………………………………………………… 75
Figure 17. Plasma samples analyzed by LC-MS in electrospray
positive ion mode, comparing EAD and nonEAD recipients by class
permutation analysis………………………………………………… 76
Figure 18. Prediction of early allograft dysfunction in study cohort... 77
Figure 19. Prediction of long hospital stay in study cohort…………. 78
Figure 20. Prediction of all-cause in-hospital mortality in study
cohort…………………………………………………………….......
79
Figure 21. Prediction of early allograft dysfunction in validation
cohort………………………………………………………………...
80
Figure 22. Prediction of long hospital stay in validation cohort…….. 81
Figure 23. Prediction of all-cause in-hospital mortality in validation
cohort ………………………………………………………………..
82
Figure 24. Schematic illustration of metabolic disturbances
associated with poor outcomes of liver transplants………………… 83


List of Tables
Table 1. Risk of malignancies in liver tranplant recipients………….. 84
Table 2. Risk of vascular disease in liver transplant recipients……... 86
Table 3. Summary of clinical data for living donor liver
transplantation recipients……………………………………………. 87
Table 4. Biochemical data for the patients before and after liver
transplantation……………………………………………………….
88
Table 5. Concentrations of amino acids at T6 in study group………. 90
Table 6. A List of metabolites that discriminated the EAD from the
non-EAD groups …………………………………………………….
91
Table 7. Receiver operating characteristic (ROC) curve analysis for
individual metabolites in study and validation group……………….
93
Table 8. Demographic details from the validation population……… 94
Table 9. Biochemical details from the validation study population… 95

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