- 學位論文
飲食介入對於肝硬化病人之肝腦病變發生的影響之統合分析及效果評估臨床試驗計劃書
Effect of dietary intervention on the prevention of hepatic encephalopathy in patients with liver cirrhosis: A meta-analysis and the clinical trial protocol to evaluate the efficacy of BCAA on the recurrence of encephalopathy.
摘要
肝腦病變（Hepatic Encephalopathy; HE）是末期肝硬化常見的併發症之一，不顯著及顯著的肝腦病變（Minimal HE, Overt HE; MHE, OHE）在整體肝硬化病人身上的累積發生率分別約為20%-80%及10%-14%，而處於失代償性肝硬化的病人更是高達每年16%-21%。致死率的部份則在嚴重的肝腦病變患者第一年發生時可高達50%。而引起肝硬化的成因很多，以台灣來說，B肝病毒及C肝病毒是造成國人肝硬化的主因。雖然，我們目前已可知感染B肝病毒及C肝病毒的人口數分別約為總人口數的<20％及8.3％及其所可能造成的危害。但對於肝腦病變更詳近的發生情況及機轉卻均尚不明確。 在肝腦病變的機轉上，現仍處在假說的階段（例如：ammonia hypothesis、gama-aminobutyric acid hypothesis等），需要更多的相關研究來找出切確的機制。而在診所上可而在診斷上可依賴理學檢查、生化檢測（Laboratory test）、神經學檢測（Neuropsychometric tests）、影像學檢查（CT, MRI）及腦波檢查（Electroencephalography; EEG）四種。之後再根據診斷結果，決定治療方式來改善肝腦病變的症狀或降低其發生率，治療上則可概分為藥物治療及手術治療兩種，藥物治療多以Lactulose為第一線治療藥物、或採用抗生素（如：Neomycin等）、降氨藥物（如：L-ornithine-L-aspartate等）等藥物做為單一或合併治療、另外也可透過經頸靜脈肝內門靜脈體循環分流術（Transjugular Intrahepatic Portosystemic Shunt; TIPS）來降低其發生。無論是透過藥物或手術治療、預後均被建議配合調整不良生活習慣及補充營養來減低或預防肝腦病變的再發生。不良生活習慣的調整包括：戒菸、多運動等，而在飲食方面則以攝取足量的蛋白期及補充特殊胺基酸（支鏈胺基；Branched-Chain Amino Acids； BCAAs）的補充做為營養治療的要點。 我們參考2017年於Cochrane發表的論文（Branched-chain amino acids for people with hepatic encephalopathy(Review)），並以該論文為基礎、以相同的搜尋條件，將2017年以後發表的隨機對照試驗資料（randomized controlled trial）或世代研究（cohort study）的資料，再次納入統合分析（Meta-analysis）、再次探討支鏈胺基酸飲食介入對於肝腦病程的影響。使用關鍵字包括：支鏈胺基酸、肝臟疾病、肝腦病變、肝硬化、纖維化。分別從電子論文搜尋系統（包括：PubMed、Web of Science、及Embase）中收集自2017年6月（含）後的隨機對照試驗資料（randomized controlled trial）及自1990年到2020年06月的世代研究資料。最後找出3篇文獻（Figure 1），再與2017年於Cochrane發表的論文中的16筆資料合併後，再重新分析結果，而分析軟體則使用Review Manager version 5.3進行結果的分析。 分析結果支鏈胺基酸的介入約可降低26％的肝腦病變的發生（Figure 2，risk ratio = 0.74）。而異質性分析的部份（Figure 2，I2=47%，Chi2/df=1.99>1)，顯示存在中度異質性。為分析異質性對結果的影響，我們透過次族群分析及刪除文獻以試圖找出異質性來源及原因。次族群分析發現異質性並不影響支鏈胺基酸的效果（Figure 4到Figure 10），而刪除文獻對於異質性變化及結果同樣並未有明顯的差異（Figure 3），我們推估是因為在不同實驗組間並未有共同的好的預測因子（predictor）加上介入（intervention）方式或參與者特性（character）二者的差異、使得異質性無法被適當的解釋。在出版偏差(publication bias)的部份，漏斗圖（Figure 11）則顯示無出版偏差的問題。 分析結果顯示對於補充BCAA對肝病進展有顯著助益，惟所納入分析的文獻均為國外研究，為了確認支鏈胺基酸與肝腦病變對於台灣人的實際影響，我們將在前瞻性(prospective)研究的部份設計一飲食介入，再次探討現行支鏈胺基酸與肝腦病變對於台灣人的影響。
並列摘要
Background and Aim: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication and remain high unpredictable in patients with liver cirrhosis. The accumulated incidence rate of hepatic encephalopathy was 10%-14% of patients with cirrhosis develop overt hepatic encephalopathy (OHE), while 20%-80% of these patients develop unrecognized or light cognitive dysfunction or minimal hepatic encephalopathy (MHE) in 2014 in the world. However, both of the incidence rates of hepatic encephalopathy of MHE or OHE is not clear. The pathogenesis of HE is still unclear, too. Among the hypothesis of HE, supplying BCAA (branched-chain amino acids) is the most natural therapy to improve HE, other therapies including medicine (such as lactulose, neomycin, L-ornithine-L-aspartate, etc.) and surgery (such as Transjugular Intrahepatic Portosystemic Shunt; TIPS). However, the effectiveness of therapy is not defined yet. We aimed to confirm the power of BCAA in patients with hepatic encephalopathy by meta-analysis. To reach the goal, we referenced a journal, which was published in Cochrane in 2017. We had used the data and the same strategy to search for the references from the journal. Finally, we collected the randomized controlled trial (RCT) from 2017 to 2020 and cohort study from 1990 to 2020. Selection criteria and search methods: 450 studies were found from Pubmed, Web of Science, and Embase. 3 eligible studies were selected finally (Figure 1). The inclusion criteria were also the same as the reference in Cochrane in 2017. The keywords we used including BCAA, liver disease, hepatic encephalopathy, cirrhosis, and fibrosis. Results: We found that BCAA can decrease the incidence of HE around 26% (Figure 2, risk ratio = 0.74, p-value <0.05). The heterogeneity of overall was moderate. (Figure 2, I2=47%，Chi2/df =1.99>1, p-value = 0.01). The subgroup analysis (Figure 4 to Figure 10) and delete the reference (Figure 3) were showed that the heterogeneity did not impact the overall result. We assumed that lack of appropriate predictors between different studies, and the difference of intervention or the character of participants, making the heterogeneity was difficult to explain. We also detect the publication bias, the funnel plot (Figure 11) was showed that the publication bias does not exist. Conclusions: Meta-analysis shows the efficacy of BCAA in patients with cirrhosis. However, most of the references are from other nations, there is no study from Taiwan and lack of sufficient study for HE patients with acute liver injury. For confirming the efficacy of BCAA in patients with cirrhosis in Taiwan, we will design a proposal with diet intervention to discuss the efficacy of BCAA in patients with cirrhosis in Taiwan.
參考文獻
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