Clinical manifestation of H1 magnetic resonance spectroscopy in non-alcoholic liver cirrhosis

磁共振頻譜分析是一種非侵襲性的檢查,用來偵測身體各部位的代謝產物.常用於醫學的核磁共振頻譜儀有氫原子(Proton)及磷31 (P31)以及氟19 (F19) 三種。氫原子頻譜最早被發展出來,常用於大腦疾病，尤其是原因不明的癲癇，急性之腦梗塞(六小時以內)，腦腫瘤治療前後的變化(Hammen et al. 2003)，均以頻譜偵測腦中化學成份及比例的改變以作為評估。由於磷的代謝與身體中的能量轉換有關,例如三磷酸腺苷(ATP),其相關代謝產物如phosphomonoesters或是phosphodiester也被用來評估相關的代謝(Munakata et al. 1993),例如偵測能量的轉變肌肉疾病及肌肉在活體運動過程中各種化學成份的變化，以及骨骼肌肉腫瘤在治療前後的改變。氟19 (F19)則被用來評估各種藥物在身體內的分佈，例如化學治療藥物5-FU在肝臟中的分佈情形(Klomp et al. 2003)。

由於人體組織的化學結構含豐富的氫原子，氫原子的磁振造影及頻譜可準確地偵測脂肪的影像及成份的評估。所以對脂肪與水分子的研究陸續發展，均以氫原子頻譜為研究方法。有幾項常用的分子指標可以作為磁共振頻譜的分析。肌酐酸(Creatine），膽素(Choline)，脂質(Lipid)，以及乳酸(Lactate)。

肝硬化患者的肝臟新陳代謝速率與正常人有許多的不同，例如研究指出Ｃ型肝炎造成的肝病變常伴有脂肪肝的變化，對於乳酸的代謝與正常人也有不同，可是利用磁共振頻譜進行肝硬化的研究相當的少見，由於磁共振頻譜不具侵襲性，若能利用磁共振頻譜進行肝硬化患者的肌酐酸，膽素，脂質，以及乳酸代謝研究，不但有可能建立無侵襲性的肝硬化診斷，更有可能根據肝硬化患者特別的代謝，進行與代謝有關的治療。

本計畫建立正常人之肝臟磁共振頻譜數據，並收集肝硬化患者的資料，檢測的部位包括肝臟右葉，內收大肌腰椎的骨髓，以及脾臟，總共收集二十八名正常受試者與十三名肝硬化患者的資料進行比對分析，分析項目包括已知的磁共振頻譜可以偵測的代謝產物如肌酐酸，膽素，脂質，以及其他可能有顯著差異的代謝產物。

研究結果發現, 肝臟磁共振頻譜可以發現脂質的訊號(0.8~2.1ppm)以及水分子的訊號,更進一步發現,在肝臟的脂質水分比在肝硬化以及正常受試者中兩者有統計上的差異（Ｐ＝0.017），正常受試者為4.07±1.08，肝硬化的患者為3.658±0.96.至於年齡(P=0.52)以及性別(P=0.74)對於此項比值並沒有影響.此項檢測的R=0.488, R square=0.188.

在脾臟的分析中, 可以發現1.4ppm的脂質與水分子的波峰寬度(width)的比值在肝硬化以及正常受試者中兩者有統計上的差異（Ｐ＝0.002），正常受試者為1.65±0.98，肝硬化的患者為2.37±0.64. 同時性別也是一個影響的因素(P=0.029),男性為1.83±0.83,女性為2.25±1.27.至於年齡(P=0.52)對於此項比值並沒有影響.

若分析骨髓的頻譜共振, 可以發現0.8 ppm的脂質的波峰面積 (AREA)在肝硬化以及正常受試者中兩者有統計上的差異（Ｐ＝0.002），正常受試者為434±316肝硬化的患者為251±85. 同時年齡也是一個影響的因素(P=0.004),年齡愈大,脂質的訊號愈強 .至於性別 (P=0.52)對於此項比值並沒有影響.

若分析大腿肌肉的各種脂質,Choline的peak width與Creatine的比值可以得到下列結果,Choline/Creatine比在肝硬化與正常受試者有顯著不同(p=0.02),正常受試者為2.17±316肝硬化的患者為1.77±0.68 同時年齡也是一個影響的因素(P=0.04),年齡愈大,Choline/Creatine的比值愈少.至於性別 (P=0.11)對於此項比值並沒有影響.

由於肝臟的氫頻譜共振分析研究相當有限,所以我們設計的這項研究來評估氫頻譜共振分析在肝臟以及其他器官的應用,並且發現氫頻譜共振分析可以用來評估病毒性肝硬化的全身代謝狀況.

Magnetic Resonance Spectroscopy (MRS) is commonly applied in medicine with 1H proton or 31phosphorus spectra. The proton MRS is often used in evaluating the central nervous system such as metabolites in epilepsy, diagnosis of brain tumor and biological change after acute ischemic stroke(Hammen et al. 2003). 31P MRS was used in muscular disease or neoplasm(Munakata et al. 1993). F19 was often used for monitoring of drug delivery to the body(Klomp et al. 2003).

Because of the richness in proton in the human body, it is advantageous to get higher signal/noise ratio from proton magnetic resonance spectroscopy. Some metabolites which are often used as indexes in proton magnetic resonance spectroscopy are creatine, lipid, choline and lactate.

Although the studies of hepatic metabolism by using proton magnetic resonance spectroscopy are limited, the metabolic behavior of the cirrhotic liver differs in certain aspects. Some reports revealed hepatic steatosis is correlated with hepatitis C related liver cirrhosis(Lonardo et al. 2004). The metabolic rate of the lactate is correlated with hepatic function. Since proton magnetic resonance spectroscopy is a non-invasive procedure, it would facilitate the diagnosis non-invasively and it will improve the knowledge of metabolic event in vivo.

The purpose of this study is to evaluate the metabolic change of non-alcoholic liver cirrhotic patients using proton magnetic resonance spectroscopy. Twenty-eight normal subjects and thirteen non-alcoholic cirrhotic patients were enrolled into this study. The peak of creatine, choline, lipid , water and lactate in MRS were analyzed and compared.

Hepatic MRS revealed water, lipid peak could be detected and there is statistical significant difference between normal subjects and cirrhotic patients in lipid(2.1 ppm)/water ratio (p=0.017). Besides, there is statistical difference in lipid(1.4 ppm)/water ratio detected by spleen MRS (p=0.002) between these two groups.

Further investigation of the bone marrow between these two groups revealed there is difference in lipid (0.8 ppm) area (p=0.002). The choline/creatine detected by muscles MRS was also different in cirrhotic and normal subjects (p=0.02).

We conclude that liver; muscle and bone marrow metabolites are different between non-alcoholic liver cirrhosis patients and normal subjects. The differences could be investigated by MRS. Magnetic resonance spectroscopy was proved to be a non-invasive method for measuring metabolites in hepatic disease.