组合型人工肝的研究进展

黄玥; 彭虹; 罗新华

doi:10.12449/JCH240203

组合型人工肝的研究进展

DOI: 10.12449/JCH240203

贵州省人民医院感染科，贵阳 550000

基金项目:

贵州省科学技术基金 (ZK［2021］Key 013)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：黄玥负责查找文献，撰写文稿；彭虹负责审阅文稿；罗新华负责审阅文稿及最后定稿。

详细信息

通信作者:
罗新华， luoxinhua1972@126.com （ORCID： 0000-0001-8285-3063）

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出版历程
- 收稿日期: 2023-10-30
- 录用日期: 2023-11-29
- 出版日期: 2024-02-19

Research advances in combined artificial liver

Department of Infectious Diseases，Guizhou Provincial People’s Hospital，Guizhou 550000，China

Research funding:

Guizhou Science and Technology Foundation (ZK［2021］Key 013)

More Information

Corresponding author: LUO Xinhua， luoxinhua1972@126.com （ORCID： 0000-0001-8285-3063）

摘要

摘要: 目前体外人工肝支持系统在各种原因导致的肝衰竭、肝移植前后无功能时期、严重胆汁性淤积等疾病中取得良好治疗效果。其中非生物型人工肝（NBAL）通过各种模式互补组合广泛应用于临床，主要以改善机体凝血因子和白蛋白等物质的血浆置换模式联合其余增强清除体内有毒物质谱的模式。以肝细胞的合成、转化功能为设计理念的生物型人工肝（BAL）近年也取得飞速发展。肝衰竭患者先经NBAL解毒后，再予以BAL合成、转化体内活性物质，能更接近人体肝脏正常生理功能。根据患者病情个体化组合NBAL模式，再结合疗效稳定的BAL是未来重症肝病患者体外支持治疗方向。
- 组合型非生物人工肝 /
- 组合型生物人工肝 /
- 治疗学
Abstract: At present， in vitro artificial liver support system has achieved a good therapeutic effect in the diseases such as liver failure due to various causes， non-function state before and after liver transplantation， and severe cholestasis. Non-bioartificial liver （NBAL） is widely used in clinical practice through various combinations of modes， mainly the plasma exchange mode for improving coagulation factors and albumin combined with other modes for enhancing the elimination of toxic substances in the body. Bioartificial liver （BAL）， based on the design concept of the synthesis and transformation of hepatocytes， has achieved rapid development in recent years. Patients with liver failure can almost obtain the normal physiological function of human liver after NBAL detoxification and BAL synthesis and transformation of active substances in the body. NBAL mode combined with BAL with a stable therapeutic effect according to the conditions of the patient is the direction of in vitro support treatment for patients with severe liver disease in the future.
- Combined Non-biological Artificial Liver /
- Combined Bioartificial Liver /
- Therapeutics

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表 1 组合型NBAL模型的优缺点^［2］

Table 1. Advantages and disadvantages of combined NBAL model

国内常见的NBAL组合模式	优点	缺点
DPMAS+PE	特异性高效吸附胆红素、清除毒素，补充凝血因子及白蛋白	无法改善肾功能，以血浆为置换液行PE时可能会加重肝性脑病
PE+HDF	毒素清除范围与程度增加，改善肾功能不全与肝性脑病，维持内环境稳定	血浆需求量较大，治疗时间相对较长
HDF+DPMAS	不需要用血浆，对胆红素、炎性介质、内毒素、中小分子水溶性毒素清除能力强	无法补充白蛋白、凝血因子等，治疗时间长
PDF+PP	减少血浆应用量，更有效地清除胆红素及其他大分子毒素，补充凝血因子及白蛋白	治疗时间长，重症患者的凝血监测与抗凝要求高
PE+PP+HDF	对大、中、小分子毒素都具有很好的清除能力，同时补充凝血因子	血浆需求量较大，治疗时间长，需给予合理的抗凝方案及监测
注：DPMAS，双重血浆分子吸附系统。

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表 2 国内外常见的BAL来源与研究进展

Table 2. Sources and research progress of common BAL

系统	细胞来源	反应器	来源	相关研究结果
国内
hiHep-BAL	转分化细胞hiHep	多层平板模型	（1） NCT05035108；（2） NCT03084198；（3）微知卓生物科技有限公司	动物肝切除模型和临床扩大肝切除患者研究中，改善肝功能，增加术后肝脏再生速度，提高存活率^［35-36］
RL1-BAL	未知	未知	NCT04195282	比较PE与RL1-BAL+PE治疗HBV-ACLF的效果与预后。目前尚无相关临床指标。具体详细情况未公布
HepAssis2-BAL	人源肝细胞HL2	中空纤维反应器	（1） ChiCTR2300075781；（2）武汉仝干医疗科技股份有限公司	相比NBAL组，BAL组的血浆用量显著减少，生化指标降低幅度两组相当，长期无肝移植存活率显著升高。（结果来源该公司官网 http：//www.whtogo.com/detail_254.html）
IHH-BAL	永生化细胞IHH	微囊悬液式	苏州瑞徕生物科技有限公司	临床试验进行中，未见相关结果展示
ZHJ-Ⅲ系统	永生化细胞HepGL	灌流式	（1） ChiCTR1800016021；（2）广州乾晖生物科技有限公司	临床前研究阶段，结果尚未公布
Aliver系统	转分化细胞HepLPC	气液交互式	上海赛立维生物科技有限公司	临床前研究阶段。Ali-Cell肝细胞的BAL可以对肝衰竭患者血浆进行代谢解毒，并合成活性物质减轻肝损伤促进肝脏再生修复^［37］
国外
LifeLiver系统	未知	未知	（1） NCT03882346；（2）韩国三星医疗HLB Cell Co.公司	目前注册的研究是关于在等待紧急肝移植的急性或ACLF患者中的安全性和有效性，未见相关结果展示
ELAD系统	人肝癌细胞株C3A细胞	中空纤维反应器	（1） NCT01875874；（2） NCT01829347；（3） Vital therapies公司	Ⅲ期临床试验中因初期疗效不佳，ELAD相关研究已提前终止，无明确结果^［38］
HepatAssist系统	猪源肝细胞	中空纤维反应器	Circe biomedical公司	该系统已进行相关临床研究，尽管研究证明没有猪逆转录病毒感染的安全性问题，但是临床疗效仍然存在争议，处于Ⅲ期临床阶段^［33］
BLSS系统	猪源肝细胞	中空纤维反应器	（1） Excorp Medical公司；（2）匹兹堡大学；（3） PubMed	与HepatAssist的区别是没有活性炭，目前在Ⅰ~Ⅱ期临床阶段^［42］
MELS系统	原代人肝细胞/猪源肝细胞	中空纤维反应器	（1）柏林堡大学；（2） PubMed	基于3D构建的人肝细胞反应器，进入Ⅱ期临床阶段，也有采用猪肝细胞反应器，初步研究排除猪逆转录病毒感染风险^［43］

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参考文献(46)

[1]	SALIBA F, BAÑARES R, LARSEN FS, et al. Artificial liver support in patients with liver failure: A modified DELPHI consensus of international experts[J]. Intensive Care Med, 2022, 48( 10): 1352- 1367. DOI: 10.1007/s00134-022-06802-1.
[2]	Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Expert consensus on clinical application of artificial liver and blood purification(2022 edition)[J]. J Clin Hepatol, 2022, 38( 4): 767- 775. DOI: 10.3969/j.issn.1001-5256.2022.04.007. 中华医学会肝病学分会重型肝病与人工肝学组. 人工肝血液净化技术临床应用专家共识(2022年版)[J]. 临床肝胆病杂志, 2022, 38( 4): 767- 775. DOI: 10.3969/j.issn.1001-5256.2022.04.007.
[3]	LI XT, YAO Y, ZHENG RJ, et al. Analysis of curative effect and short-term survival rate of plasma exchange and double plasma molecular adsorption combined with half-volume plasma exchange in the treatment of liver failure[J]. Chin J Hepatol, 2023, 31( 7): 736- 741. DOI: 10.3760/cma.j.cn501113-20230228-00083. 李新婷, 姚瑶, 郑嵘炅, 等. 血浆置换与双重血浆分子吸附联合半量血浆置换对肝衰竭治疗的疗效及短期生存率分析[J]. 中华肝脏病杂志, 2023, 31( 7): 736- 741. DOI: 10.3760/cma.j.cn501113-20230228-00083.
[4]	WU C, PENG W, CHENG D, et al. Efficacy and economic evaluation of nonbiological artificial liver therapy in acute-on-chronic hepatitis B liver failure[J]. J Clin Transl Hepatol, 2023, 11( 2): 433- 440. DOI: 10.14218/JCTH.2022.00106.
[5]	GAO Q, CHEN J, ZHAO C, et al. Combination of plasma exchange and adsorption versus plasma exchange in pediatric acute liver failure: A multicenter cohort study[J]. J Pediatr Gastroenterol Nutr, 2023, 76( 6): 710- 715. DOI: 10.1097/MPG.0000000000003759.
[6]	YANG CF, ZHANG Z, ZHANG XY, et al. Artificial liver support system in pediatric acute liver failure due to mushroom poisoning: Case series[J]. Ann Hepatol, 2021, 23: 100290. DOI: 10.1016/j.aohep.2020.100290.
[7]	TAN YW, SUN L, ZHANG K, et al. Therapeutic plasma exchange and a double plasma molecular absorption system in the treatment of thyroid storm with severe liver injury: A case report[J]. World J Clin Cases, 2019, 7( 10): 1184- 1190. DOI: 10.12998/wjcc.v7.i10.1184.
[8]	ZHOU J, WANG XX, LIAN JS, et al. Comparison of efficacy and safety between artificial liver plasma dia-filtration(PDF) and plasma exchange with continuous veno-venous hemofiltration(FPE+CVVH) for mid and late stage liver failure[J]. Chin J Clin Infect Dis, 2018, 11( 5): 369- 373. DOI: 10.3760/cma.j.issn.1674-2397.2018.05.008. 周健, 王笑笑, 连江山, 等. 人工肝血浆透析滤过与选择性血浆置换联合连续性血液滤过治疗中晚期肝衰竭疗效及安全性比较[J]. 中华临床感染病杂志, 2018, 11( 5): 369- 373. DOI: 10.3760/cma.j.issn.1674-2397.2018.05.008.
[9]	NAKAE H, IGARASHI T, TAJIMI K, et al. A case report of hepatorenal syndrome treated with plasma diafiltration(selective plasma filtration with dialysis)[J]. Ther Apher Dial, 2007, 11( 5): 391- 395. DOI: 10.1111/j.1744-9987.2007.00505.x.
[10]	DUAN W, XIAO ZH, YANG LG, et al. Kikuchi’s disease with hemophagocytic lymphohistiocytosis: A case report and literature review[J]. Medicine, 2020, 99( 51): e23500. DOI: 10.1097/MD.0000000000023500.
[11]	OIWA H, YOSHIDA S, OKADA H, et al. Atypical drug-induced hypersensitivity syndrome with multiple organ failure rescued by combined acute blood purification therapy: A case report[J]. Int J Emerg Med, 2023, 16( 1): 33. DOI: 10.1186/s12245-023-00511-2.
[12]	EGUCHI Y. Plasma dia-filtration for severe sepsis[J]. Contrib Nephrol, 2010, 166: 142- 149. DOI: 10.1159/000314864.
[13]	KOMURA T, TANIGUCHI T, SAKAI Y, et al. Efficacy of continuous plasma diafiltration therapy in critical patients with acute liver failure[J]. J Gastroenterol Hepatol, 2014, 29( 4): 782- 786. DOI: 10.1111/jgh.12440.
[14]	KINJO N, HAMADA K, HIRAYAMA C, et al. Role of plasma exchange, leukocytapheresis, and plasma diafiltration in management of refractory macrophage activation syndrome[J]. J Clin Apher, 2018, 33( 1): 117- 120. DOI: 10.1002/jca.21570.
[15]	INOUE N, SATO A, IKAWA Y, et al. Successful treatment of exertional heat stroke using continuous plasma diafiltration[J]. J Clin Apher, 2016, 31( 5): 490- 492. DOI: 10.1002/jca.21439.
[16]	LI K, YANG XL, YANG DK. Effects of three modes of artificial liver therapy on liver function, coagulation function and survival rate in patients with acute liver failure[J]. China J Prac Med, 2020, 47( 16): 55- 58. DOI: 10.3760/cma.j.cn115689-20200507-02155. 李剀, 杨晓莉, 杨道坤. 三种模式非生物型人工肝对急性肝衰竭患者肝功能、凝血功能及生存率的影响[J]. 中国实用医刊, 2020, 47( 16): 55- 58. DOI: 10.3760/cma.j.cn115689-20200507-02155.
[17]	LALEMAN W, WILMER A, EVENEPOEL P, et al. Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure[J]. Crit Care, 2006, 10( 4): R108. DOI: 10.1186/cc4985.
[18]	HASSANEIN TI, TOFTENG F, BROWN RS Jr, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis[J]. Hepatology, 2007, 46( 6): 1853- 1862. DOI: 10.1002/hep.21930.
[19]	MITZNER SR, STANGE J, KLAMMT S, et al. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: Results of a prospective, randomized, controlled clinical trial[J]. Liver Transpl, 2000, 6( 3): 277- 286. DOI: 10.1002/lt.500060326.
[20]	GERTH HU, POHLEN M, THÖLKING G, et al. Molecular adsorbent recirculating system can reduce short-term mortality among patients with acute-on-chronic liver failure-a retrospective analysis[J]. Crit Care Med, 2017, 45( 10): 1616- 1624. DOI: 10.1097/CCM.0000000000002562.
[21]	SALIBA F, CAMUS C, DURAND F, et al. Albumin dialysis with a noncell artificial liver support device in patients with acute liver failure: A randomized, controlled trial[J]. Ann Intern Med, 2013, 159( 8): 522- 531. DOI: 10.7326/0003-4819-159-8-201310150-00005.
[22]	MACDONALD AJ, SUBRAMANIAN RM, OLSON JC, et al. Use of the molecular adsorbent recirculating system in acute liver failure: Results of a multicenter propensity score-matched study[J]. Crit Care Med, 2022, 50( 2): 286- 295. DOI: 10.1097/CCM.0000000000005194.
[23]	BAÑARES R, IBÁÑEZ-SAMANIEGO L, TORNER JM, et al. Meta-analysis of individual patient data of albumin dialysis in acute-on-chronic liver failure: Focus on treatment intensity[J]. Therap Adv Gastroenterol, 2019, 12: 1756284819879565. DOI: 10.1177/1756284819879565.
[24]	SCHAEFER B, SCHAEFER F, WITTMER D, et al. Molecular adsorbents recirculating system dialysis in children with cholestatic pruritus[J]. Pediatr Nephrol, 2012, 27( 5): 829- 834. DOI: 10.1007/s00467-011-2058-8.
[25]	RIFAI K. Fractionated plasma separation and adsorption: Current practice and future options[J]. Liver Int, 2011, 31( Suppl 3): 13- 15. DOI: 10.1111/j.1478-3231.2011.02595.x.
[26]	SENTÜRK E, ESEN F, OZCAN PE, et al. The treatment of acute liver failure with fractionated plasma separation and adsorption system: Experience in 85 applications[J]. J Clin Apher, 2010, 25( 4): 195- 201. DOI: 10.1002/jca.20238.
[27]	KRIBBEN A, GERKEN G, HAAG S, et al. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure[J]. Gastroenterology, 2012, 142( 4): 782- 789. DOI: 10.1053/j.gastro.2011.12.056.
[28]	RIFAI K, BODE-BOEGER SM, MARTENS-LOBENHOFFER J, et al. Removal of asymmetric dimethylarginine during artificial liver support using fractionated plasma separation and adsorption[J]. Scand J Gastroenterol, 2010, 45( 9): 1110- 1115. DOI: 10.3109/00365521.2010.485322.
[29]	RIFAI K, HAFER C, ROSENAU J, et al. Treatment of severe refractory pruritus with fractionated plasma separation and adsorption(Prometheus)[J]. Scand J Gastroenterol, 2006, 41( 10): 1212- 1217. DOI: 10.1080/00365520600610154.
[30]	BERGIS D, FRIEDRICH-RUST M, ZEUZEM S, et al. Treatment of Amanita phalloides intoxication by fractionated plasma separation and adsorption(Prometheus^®)[J]. J Gastrointestin Liver Dis, 2012, 21( 2): 171- 176.
[31]	VARDAR R, GUNSAR F, ERSOZ G, et al. Efficacy of fractionated plasma separation and adsorption system(Prometheus) for treatment of liver failure due to mushroom poisoning[J]. Hepato-gastroenterology, 2010, 57( 99-100): 573- 577.
[32]	LI LJ, YANG Q, HUANG JR, et al. Study of severe hepatitis treated with a hybrid artificial liver support system[J]. Chin J Dial Artif Organs, 2004, 15( 1): 21- 24. 李兰娟, 杨芊, 黄建荣, 等. 混合型人工肝支持系统治疗慢性重型肝炎疗效研究[J]. 透析与人工器官, 2004, 15( 1): 21- 24.
[33]	DEMETRIOU AA, BROWN RS Jr, BUSUTTIL RW, et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure[J]. Ann Surg, 2004, 239( 5): 660-667; discussion 667-670. DOI: 10.1097/01.sla.0000124298.74199.e5.
[34]	ZHANG Z, ZHAO YC, CHENG Y, et al. Hybrid bioartificial liver support in cynomolgus monkeys with D-galactosamine-induced acute liver failure[J]. World J Gastroenterol, 2014, 20( 46): 17399- 17406. DOI: 10.3748/wjg.v20.i46.17399.
[35]	WANG Y, ZHENG Q, SUN Z, et al. Reversal of liver failure using a bioartificial liver device implanted with clinical-grade human-induced hepatocytes[J]. Cell Stem Cell, 2023, 30( 5): 617- 631. DOI: 10.1016/j.stem.2023.03.013.
[36]	SHI XL, GAO Y, YAN Y, et al. Improved survival of porcine acute liver failure by a bioartificial liver device implanted with induced human functional hepatocytes[J]. Cell Res, 2016, 26( 2): 206- 216. DOI: 10.1038/cr.2016.6.
[37]	LI WJ, ZHU XJ, YUAN TJ, et al. An extracorporeal bioartificial liver embedded with 3D-layered human liver progenitor-like cells relieves acute liver failure in pigs[J]. Sci Transl Med, 2020, 12( 551): eaba5146. DOI: 10.1126/scitranslmed.aba5146.
[38]	KINASIEWICZ A, GAUTIER A, LEWISKA D, et al. Three-dimensional growth of human hepatoma C3A cells within alginate beads for fluidized bioartificial liver[J]. Int J Artif Organs, 2008, 31( 4): 340- 347. DOI: 10.1177/039139880803100411.
[39]	LEE JH, LEE DH, LEE S, et al. Functional evaluation of a bioartificial liver support system using immobilized hepatocyte spheroids in a porcine model of acute liver failure[J]. Sci Rep, 2017, 7( 1): 3804. DOI: 10.1038/s41598-017-03424-2.
[40]	CHEN HS, JOO DJ, SHAHEEN M, et al. Randomized trial of spheroid reservoir bioartificial liver in porcine model of posthepatectomy liver failure[J]. Hepatology, 2019, 69( 1): 329- 342. DOI: 10.1002/hep.30184.
[41]	LI Y, WU Q, WANG Y, et al. Novel spheroid reservoir bioartificial liver improves survival of nonhuman Primates in a toxin-induced model of acute liver failure[J]. Theranostics, 2018, 8( 20): 5562- 5574. DOI: 10.7150/thno.26540.
[42]	KUDDUS R, PATZER JF 2nd, LOPEZ R, et al. Clinical and laboratory evaluation of the safety of a bioartificial liver assist device for potential transmission of porcine endogenous retrovirus[J]. Transplantation, 2002, 73( 3): 420- 429. DOI: 10.1097/00007890-200202150-00017.
[43]	GERLACH JC. Bioreactors for extracorporeal liver support[J]. Cell Transplant, 2006, 15( Suppl 1): S91- S103. DOI: 10.3727/000000006783982296.
[44]	POYCK PP, PLESS G, HOEKSTRA R, et al. In vitro comparison of two bioartificial liver support systems: MELS CellModule and AMC-BAL[J]. Int J Artif Organs, 2007, 30( 3): 183- 191. DOI: 10.1177/039139880703000302.
[45]	CALISE F, MANCINI A, AMOROSO P, et al. Functional evaluation of the AMC-BAL to be employed in a multicentric clinical trial for acute liver failure[J]. Transplant Proc, 2001, 33( 1-2): 647- 649. DOI: 10.1016/s0041-1345(00)02183-7.
[46]	ADAM AAA, van WENUM M, van der MARK VA, et al. AMC-Bio-Artificial Liver culturing enhances mitochondrial biogenesis in human liver cell lines: The role of oxygen, medium perfusion and 3D configuration[J]. Mitochondrion, 2018, 39: 30- 42. DOI: 10.1016/j.mito.2017.08.011.