臺灣博碩士論文加值系統

臨床上發現，併發症是造成肝硬化病人死亡最主要的因素。在所
有併發症中，以腹水最為常見。所有肝硬化腹水的病患都有可能發展
為自發性細菌性腹膜炎 (spontaneous bacterial peritonitis，SBP)。根據
流行病學研究，SBP 的發生率在肝硬化腹水病患中高達 30%。近二
十年來，由於頭孢黴素類抗生素的使用，使得 SBP 的死亡率從一開
始的 100% 下降至 30%。而在後續的研究中更進ㄧ步地發現，同時
給予 SBP 患者注射抗生素與人類白蛋白，能夠降低病人腎衰竭的發
生率，並減少病人的死亡率。儘管如此，目前臨床上對於是否使用人
類白蛋白製劑仍然存在相當大的爭議，主要是因為人類白蛋白是由人
類血漿中萃取出來，所以其來源有限、價格昂貴、可能有潛在傳染的
危險。再加上先前文獻指出，給予重症病人注射人類白蛋白製劑不僅
效果不彰、且反而會增加患者之死亡率。因此，本研究欲使用較小劑
量 (約先前文獻使用劑量的五分之一) 的人類白蛋白合併抗生素使用
來治療肝硬化併發自發性細菌性腹膜炎病患。藉由監測病人的肝、腎
功能指數及相關發炎因子，我們發現單獨使用抗生素或是人類白蛋白
對於 SBP 或是 non-SBP 肝硬化腹水的病人皆無明顯的效用。相反
地，合併靜脈注射抗生素及小劑量人類白蛋白能夠有效地降低病人血
液中 TNF-α、IL-6 及腹水中endotoxin、TNF-α 和 IL-6 的濃度；並
且有效阻止腹水及血液中 NO 濃度大幅上升，同時亦能避免 SBP 病
人的腎功能進一步的惡化。此正面的結果已為在更多病人的大型試驗
上奠定一良好的根基。

In clinical findings, complications are the major cause of death in
cirrhotic patients. Among all the complications, ascites is most frequent
type. All cirrhotic patients with ascites could develop spontaneous
bacterial peritonitis (SBP). The hospitalized prevalence of SBP was high
(30%) in cirrhotic ascites patients. However, the outcome of cirrhotic
SBP patients has been improved because of using the antibiotics
cephalosporins. Furthermore, treatment with intravenous albumin in
addition to cephalosporins reduced the incidence of renal impairment and
the mortality in SBP patients in a multicentre study. However, other
studies showed that administration of albumin might not work as
effectively as other plasma expanders do. Moreover, administration of
large volume albumin would make the medication very expensive and
might have potential risk of infectious disease, since the therapeutic
albumin is extracted from human plasma. Therefore, to treat patients with
large volume albumin become disputable. In this study, we evaluated the
effects of small volume intravenous albumin with cephalosporins
treatments through monitoring patients’ renal and hepatic functions and
related inflammatory markers. Results showed that plasma TNF-α, ΙL-6
and ascites endotoxin, TNF-α and IL-6 levels were significantly reduced
in patients treated with cephalosporins plus small volume albumin, but
not in those treated with cephalosporins alone. Also, the combination
therapy of cephalosporins and small volume albumin avoid the
dramatically elevation of plasma and ascites nitric oxide, as well as the
further degree of renal function impairment. The positive results of this
study laid a solid foundation for a large scale investigation.

中文摘要………………………………………………………………... i
英文摘要………………………………………………………………... ii
縮寫表…………………………………………………………………... iii
壹、序論…………………………………………………………………. 1
1. 肝硬化 (Cirrhosis)……………………………………………… 1
1-1. 肝硬化之分類……………………………………………… 2
1-2. 肝硬化之病程與症狀……………………………………… 3
2. 腹水 (Ascitic fluid；Ascites)…………………………………… 4
2-1. 腹水的形成.………………………………………………... 4
2-2. 腹水形成的機轉…………………………………………… 5
2-3. 腹水的評估及治療………………………………................ 7
3. 自發性細菌性腹膜炎 (Spontaneous bacterial peritonitis)…….. 9
3-1. 自發性細菌性腹膜炎的病理機轉……………………........ 9
3-2. 內毒素 (Endotoxins；LPS) 及細菌 DNA (bacDNA)…….. 10
3-3. 細胞素 (Cytokines)………………………………………... 12
3-4. 一氧化氮 (Nitric oxide, NO)………………………………. 14
3-5. 自發性細菌性腹膜炎的臨床診斷及檢測………………… 16
4. 自發性細菌性腹膜炎的治療…………………………………… 19
4-1. 抗生素 (Antibioics)………………………………………... 19
4-2. 人類白蛋白 (Human albumin).............................................. 21
貳、研究目的……………………………………………………………. 24
叁、實驗材料及方法……………………………………………………. 25
1. 實驗樣本……………………………………………………........ 25
2. 內毒素檢測……………………………………………………... 26
3. TNF-α 測定……………………………………………………… 29
4. IL-6 測定…….………………………………………………….. 31
5. Nitric oxide 測定………………………....................................... 34
6. 血清中細菌DNA 之抽取………………………………………. 37
7. PCR 反應 ………………………………………………………. 38
8. 核酸定序………………………………………………………… 41
9. 統計分析………………………………………………………… 43
肆、結果………………………………………………………………… 44
1. 肝硬化腹水及自發性細菌性腹膜炎病人組別之生理特性…… 44
2. 自發性細菌性腹膜炎治療前後肝功能及腎功能的比較............ 46
3. 自發性細菌性腹膜炎病人治療前後發炎性物質的比較……… 48
4. 自發性細菌性腹膜炎病人治療前後一氧化氮濃度的比較…… 50
5. 不同組別中 SBP 的緩解率及病人死亡率之比較…………….. 52
6. 內毒素、發炎性細胞素及 NO 的相關與迴歸………………… 53
7. bacDNA 檢驗方法的特異性、敏感度…………………………. 56
7-1. 特異性 (Specificity)……………………………………….. 56
7-2. 敏感度 (Sensitivity)……………………………………….. 57
8. bacDNA 檢測方法的陽性率及序列比對結果………………… 58
9. bacDNA 與細菌培養結果的檢出率之比較…………………… 58
伍、討論………………………………………………………………… 61
陸、參考文獻…………………………………………………………… 68
柒、附錄………………………………………………………………… 75
附錄一、病人原始資料及實驗結果………………………………. 75
Table 1. 肝硬化腹水及自發性細菌性腹膜炎病人組別之生理特性… 45
Table 2. 三組病人治療前後肝功能及腎功能的變化………………… 47
Table 3. 三組病人治療前後血液及腹水中endotoxin、TNF-α、IL-6
的變化.......................................................................................
49
Table 4. 第一、二組病人治療後 SBP 緩解率及住院死亡率之比較... 52
Table 5. 腹水與血漿中 endotoxin、TNF-α、IL-6 及 NO 濃度之相
關性…………………………………………………………..
54
Table 6. 腹水或血漿中 PMN、endotoxin、TNF-α、IL-6 及 NO 濃
度彼此間之相關性……………………………………….......
55
Table 7. bacDNA 及細菌培養之鑑定結果…………………………… 59
Table 8. bacDNA 與細菌培養結果的陽性率之比較……………….. 60
Figure 1. 三組病人治療前後腹水及血液一氧化氮濃度的變化…….. 51
Figure 2. bacDNA PCR 試驗之特異性………………………………… 56
Figure 3. bacDNA PCR 試驗之敏感度………………………………… 57

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