敝人從事血液透析洗肝治療看盡生命的無奈，借此提供肝臟治療相關知識。

新型人工肝臟 ---- MARS®

 (Molecular Adsorbents Recirulating System分子吸附循環系統) MARS®的背景

MARS®人工肝臟支持療法為德國Rostock大學主持的德國聯邦科學和教育部重點基金課題,由該大學肝臟病研究中心 Stange 和 Mitzner 博士等,研究開發專為各型肝臟病人提供成功解決方案的最新型人工肝臟支持治療系統,被英國皇家肝病研究中心推薦作為治療各類肝衰竭的標準方案[1,2]。

MARS®治療使用分子吸附再循環系統,治療急、慢性肝病引起的肝衰竭,主要是支持性替代肝臟解毒功能,清除肝衰竭時累積的大量水溶性和蛋白質結合毒素,減少血漿毒素,使肝細胞再生恢復以改善病人情況,其目的是使病人完全恢復或渡過危險期以及準備和過渡到肝臟移植或避免再次肝臟移植。

MARS®的治療機制

在肝衰竭患者中因肝臟解毒功能不足,親脂性蛋白結合毒素在血液中大量累積,通常血液透析或血漿置換對於選擇性分離清除毒素-特別是對於血液中以配體方式結合的毒素物質進行分離清除是很困難的。而先進的MARS®技術可以有選擇性和有效地清除血液中各種肝臟毒性物質,使用MARS®技術可以使這些親脂性、蛋白結合毒素,不斷地被吸附在透析膜的一側,然後在膜的另一側連續地被分子吸附並選擇性清除,而在透析過程中再生循環利用(圖1)。

(圖1)                                                                (圖2)

通過半透膜 MARS®可以選擇性和有效的清除肝衰竭毒素(蛋白結合毒素)和水溶性毒素(圖2),同時體內的白蛋白以及各種有益物質則被保留而不會流失。

病人的血液通過一個血液透析器進行體外循環；膜的外側則循環著白蛋白溶液,血液中的肝臟毒素通過MARS®(模擬肝細胞膜)與對側的透析白蛋白結合而通過,然後這些結合毒素的溶液在一個含有高效吸附裝置的管路循環中解毒(模擬肝臟解毒),並通過常規透析(腎臟替代)而完全再生淨化了的白蛋白溶液,對跨膜毒素不斷進行循環清除這個機制,使MARS®在威脅生命的肝衰竭中有效地替代肝臟的解毒功能,並可以同時進行腎臟支持治療(圖1)。

目前研究證實的MARS®可以有效清除的各類蛋白結合和水溶性毒素包括

MARS®系統的先進優勢

●高效模擬肝細胞的生物解毒過程[20,21,22]

●有效清除蛋白結合毒素和水溶性毒素[3,4,6,12,13,16,20,21,23,24]

●同時具備人工腎臟功能調節水份電解質酸鹼血糖等內環境平衡[2,4,6,15,16,19,24,25,26]

●由於蛋白循環作用的機制使治療經濟有效[3,7,21,22]

●與標準透析設備相匹配準備和治療操作簡便節省人工[3,4,7,11,16]

●高度生物相容性高選擇性無細胞操作[3,7,16,20,22,23,24]

●與其它人工肝臟相比更少的副作用和醫源性風險[7,11,22]

MARS®治療的臨床作用

MARS®人工肝臟治療可以有效穩定改善肝衰竭病人的病情為肝細胞再生恢復創造條件為肝臟移植贏得時間並提高成功率

MARS®治療的臨床作用包括

●提高生存率[1,3,6,11,13,16,19, 23,24,25,26]

●成功的肝臟移植橋樑[1,3,7,9,13,23,24,25,26]

●有效改善病人的血流動力學[1,3,6,13,15,24,26,27]

●有效治療病人神經學(肝性腦病變症)[1,3,5,6,7,8,9,11,13,14,16,19,23,24,26,27,28]

●降低顱內壓[3,4,16,28]

●治療肝內膽汁淤積[3,6,9,10,11,13,19,24,26]

●治療改善腎功能[1,2,3,4,6,13,16,19,24,25,26,29]

●治療改善肝功能[3,4,6,13,19,24,26]

●消退腹水[24]

●解毒作用[1,3,6,8,10,11,13,14,21,23,24]

●提高體內白蛋白生理效力[3,13,21]

●管理水電解質等的內環境平衡[3,13,24,26]

●改善慢性膽汁淤積綜合症患者的生活質量[10]

MARS®治療的臨床適應症

I慢性肝病急性惡化(慢肝急衰)[3,4,6,11,13,15,16,20,15,23,24,26,27,29]

1. 病毒感染(慢性B肝/C肝其它易感病毒)或慢性肝病基礎上的重複感染

2. 酒精性肝炎(酒精性肝硬化肝功能代謝失償)

3. 自體免疫性疾病(慢性活動性自身免疫性肝炎PBC、PSC等)

4. 代謝異常(血色素沉著病)

5. 隱性肝硬化

及併發症

1. 進行性膽汁淤積

2. 肝性腦病變

3. 腎功能不全/肝腎症候群

4. 自發性細菌腹膜炎嚴重感染敗血症

5. 門脈高壓食道靜脈曲張破裂出血難治性腹水

6. 血液動力學異常(低動脈血壓)

7. 多重性器官衰竭

II急性/猛暴性肝衰竭[3,4,7,9,11,13,19,20,23,24,28]

1.病毒感染(慢性A型/B型/E型其它易感病毒)

2.中毒(過量毒菇中毒氟烷等)

3.各種情況下的多重器官衰竭(如嚴重病毒敗血症引起的)

4.血管原因性(如Budd Chiari 綜合症)

5.肝臟缺血再灌注損傷 - 缺血性肝炎(手術後腫瘤壓迫阻塞肝臟動脈)

6.其它原因(妊娠急性脂肪肝/Reye’綜合症)

7.其它原因不明性(隱原性)

及併發症

1.肝性腦病變

2.腎功能不全/肝腎綜合症

3.自發性細菌腹膜炎

4.血液動力學不穩定(低動脈血壓)

5.多重器官衰竭

III原發性移植肝臟無功能[3,4,7,24,28]

1.在肝移植期間灌注不充分

2.在肝移植後血管功能不全

3.在準備運輸或移植期間器官的損傷

IV肝臟手術後肝臟功能衰竭[7,23,28]

1.肝臟腫瘤術後/肝切除後

2.化學性栓塞/放射消融術後

3.活體相關的部分肝移植

4.其它手術介入(如術後局部缺血性肝炎)

V其它

1.如膽汁淤積症的頑固性搔癢等[9,10]

MARS®治療的醫療經濟學優勢

節約醫療成本

􀂋 減少了用於治療腎衰竭或水電解質失衡所需的常規血液透析治療量[2,3,4,5,7,11,19,24,25,26]

􀂋 減少了白蛋白新鮮血及血漿凝血因子的臨床使用量[3,7,11]

􀂋 減少抗生素的投用量[3,4,23,24]

􀂋 縮短了病人ICU的停留時間[4,7,11,13,24,25,28]

􀂋 由於更少的副作用和杜絕輸血(漿)感染可能，減少了醫療性糾紛訴訟成本[8,21]

提高生活質量

􀂋 減少院內死亡率[2,3,4,6,7,11,13,19,23,24,26]

􀂋 縮短住院時間[3,10]

􀂋 改善病人的長程病情主觀生活感受[3,10]

􀂋 減少整個病程的住院必要次數[3,10]  

参考文獻 1. Jalan R, Williams R. Acute-on-Chronic Liver Failure: Pathophysiological basis of therapeutic options. Blood Purif 2002;20:252-261 2. Kapoor D, Williams R, Jalan R. MARS: a new treatment for hepatorenal failure. Molecular adsorbent and recirculating system. Gastroenterology 2000 Dec;119(6):1799-800 3. Mitzner S, Stange J, Klammt S, Peszynski P, Schmidt R. Albumin dialysis using the molecular recirculating system. Curr Opin Nephr Hyp 2001;10:777-83 4. Awad SS, Swaniker F, Magee J, Punch J, Bartlett RH. Results of a phase I trial evaluating a liver support device utilizing albumin dialysis. Surgery 2001 Aug;130(2):354-62 5. Jalan R, Williams R. Improvement of cerebral perfusion after MARS therapy: Further clues about the pathogenesis of hepatic encephalopathy? Liver Transpl 2001 Aug;7(8):713-5 6. Stange J, Mitzner S, Klammt S, Loock J, Treichel U, Gerken G, Schmidt R, Liebe S. New extracorporeal liver support for chronic liver disease complicated by cholestasis – results of a prospective controlled randomized two center trial. J Hepatology 2001; 34 SI: 45 A1289 7. Novelli G, Rossi M, Pretagostini R, Poli L, Peritore D, Berloco P, Di Nicuolo A, Iappelli M, Cortesini R. Use of MARS in the treatment of acute liver failure: preliminar monocentric experience. Transplant Proc 2001 Feb-Mar;33(1-2):1942-4 8. Loock J, Stange J , Mitzner S , Schmidt R, Keefer EW, Gross GW. Influence of albumin dialysis (MARS) on neuronal network activity in-vitro Z Gastroenterol 2001:39 S2: 28-32 9. Gaspari, Pennisi, Mignani, Gasbarrini, Mercurio, Di Campli, Conti, Gentiloni . Albumin dialysis MARS: clinical results in the treatment of hepatic failure in a patient affected by NASH Z Gastroenterol 2001:39 S2: 15-17 10. Huster D, Schubert C, Achenbach H , Caca K, Mössner J, Berr F. Successful Clinical Application of Extracorporal Albumin Dialysis in a Patient with Benign Recurrent Intrahepatic Cholestasis (BRIC). Z Gastroenterol 2001:39 S2: 13-14 11. Stange J, Mitzner SR, Klammt S, Freytag J, Peszynski P, Loock J, Hickstein H, Korten G, Schmidt R, Hentschel J, Schulz M, Lohr M, Liebe S, Schareck W, Hopt UT. Liver support by extracorporeal blood purification: a clinical observation. Liver Transpl 2000 Sep;6(5):603-13 12. Awad SS, Rich PB, Kolla S, Younger JG, Reickert CA, Downing VP, Bartlett RH. Characteristics of an albumin dialysate hemodiafiltration system for the clearance of unconjugated bilirubin. ASAIO 1997; 43: M745-M749. 13. Mitzner SR, Stange J, Klammt S, Peszynski P, Schmidt R, Noldge-Schomburg G. Extracorporeal detoxification using the molecular adsorbent recirculating system for critically ill patients with liver failure. J Am Soc Nephrol 2001 Feb;12 Suppl 17:S75-82 14. Peszynski, Stange, Mitzner, Klammt, Majcher-Peszynska, Wacke, Drewelow, Schmidt. Removal of Benzodiazepine-like Substances as a Cause of Improvement of Hepatic Encephalopathy during Albumin Dialysis. Z Gastroenterol 2001:39 S2: 53 15. Schmidt LE, Sørensen VR, Svendsen LB, Hansen BA, Larsen FS. Hemodynamic changes during a single treatment with the Molecular Adsorbent Recirculating System in patients with Acute-on-Chronic Liver Failure. Liver Transpl 2001;7:1034-1039

16. Sorkine P, Ben Abraham R, Szold O, Biderman P, Kidron A, Merchav H, Brill S, Oren R. Role of the molecular adsorbent recycling system (MARS) in the treatment of patients with acute exacerbation of chronic liver failure. Crit Care Med 2001 Jul;29(7):1332-6 17. Awad SS, Sawada S, Soldes OS, Rich PB, Klein R, Alarcon WH, Wang SC , Bartlett RH. Can the clearance of tumor necrosis factor alpha and interleukin 6 be enhanced using an albumin dialysate hemodiafiltration system? ASAIO J 1999 Jan-Feb;45(1):47-9 18. Majcher-Peszynska, Peszynski, Müller, Klammt, Wacke, Mitzner, Stange, Mundkowski, Hehl, Schmidt, Drewelow Drugs in liver disease and during albumin dialysis – MARS. Z Gastroenterol 2001:39 S2: 33-35 19. McIntyre CW, Fluck RJ, Freeman JG, Lambie SH. Use of albumin dialysis in the treatment of hepatic and renal dysfunction due to paracetamol intoxication. Nephrol Dial Transplant 2002;17:316-317 20. Adham M. Methods of Extracorporeal Liver Support For Treatment of Liver Cell Failure. Z Gastroenterol 2001:39 S2: 1-5 21. Klammt, Brinkmann, Mitzner, Munzert, Loock, Stange, Emmrich, Liebe. Albumin Binding Capacity (ABiC) – a new approach for assessment of albumin transport function and its potential clinical use. Z Gastroenterol 2001:39 S2: 24-27 22. Emerson TE Jr. Unique features of albumin: a brief review. Crit Care Med 1989 Jul;17(7):690-4 23. Lamesch P, Jost U, Schreiter D, Scheibner L, Beier O, Fangmann J, Hauss J. Molecular Adsorbents Recirculating System in patients with liver failure. Transplant Proc 2001;33:3480-3482 24. Mitzner S, Klammt S, Peszynski P, Hickstein H, Korten G, Stange J, Schmidt R. Improvement of Multiple Organ Functions in Hepatorenal Syndrome During Albumin Dialysis with the Molecular Adsorbent Recirculating System. Ther Apher 2001;5(5):417-22 25. Mullen KD. Treatment of hepatorenal syndrome: lessons from the MARS trial. Hepatology 2002 Feb; 35(2): 492-493 26. Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader BD, Berger ED, Lauchart W, Peszynski P, Freytag J, Hickstein H, Loock J, Lohr JM, Liebe S, Emmrich J, Korten G, Schmidt R. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. Liver Transpl 2000 May;6(3):277-86 27. Schmidt LE, Svendsen LB, Sorensen VR, Hansen BA, Larsen FS. Cerebral blood flow velocity increases during a single treatment with the molecular adsorbents recirculating system in patients with acute on chronic liver failure. Liver Transpl 2001 Aug;7(8):709-12 28. Abraham RB, Szold O, Merhav H, Biderman P, Kidron A, Nakache R, Oren R, Sorkine P. Rapid resolution of brain edema and improved cerebral perfusion pressure following the molecular adsorbent recycling system in acute liver failure patients. Transplant Proc 2001 Sep;33(6):2897-9 29. Dagher L, Moore K. Review: The Hepatorenal Syndrome. Gut 2001;49:729-7375