Clinical efficacy of low-dose plasma exchange combined with double plasma molecular absorption system/hemoperfusion in treatment of acute-on-chronic liver failure
Objective To investigate the clinical efficacy of low-dose plasma exchange (PE) combined with artificial liver in the treatment of acute-on-chronic liver failure (ACLF) and its effect on mortality rate after stratification.Methods A total of 272 ACLF patients who were admitted to Department of Infection and Hepatology, The First Affiliated Hospital of Kunming Medical University, from January 2018 to December 2020 were enrolled and divided into low-dose PE+double plasma molecular absorption system (DPMAS)/hemoperfusion (HP) group (n=190) and medical treatment group(n=82). Laboratory markers were collected before and after treatment, and clinical outcome was compared between the two groups; stratified analysis (early stage, early-middle stage, late stage or types A, B, C) was performed for the two groups according to Diagnostic and treatment guidelines for liver failure (2018 edition), and all patients were followed up to observe general status and death at 12 weeks (short-term) and 48 weeks (long-term) after discharge. The independent samples t-test was used for comparison of normally distributed continuous data between two groups, and the paired samples t-test was used for comparison before and after treatment; the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the Wilcoxon test was used for comparison before and after treatment; the chi-square test was used for comparison of categorical data between groups.Results Both low-dose PE combined with DPMAS/HP and medical treatment alone could reduce the levels of alanine aminotransferase (ALT), aspartate aminotransferase, total bilirubin (TBil), and blood ammonia and increase the level of albumin (Alb), and both groups had significant changes in these indices after treatment (all P < 0.05). Compared with medical treatment alone, low-dose PE combined with DPMAS/HP better reduced ALT, TBil, and blood ammonia and improved Alb, with significant changes in these indices after treatment (all P < 0.05). Low-dose PE combined with DPMAS/HP could significantly reduce bile acid, international normalized ratio, neutrophil-lymphocyte ratio, and MELD score and increase platelet-to-white blood cell ratio (all P < 0.05), while medical treatment alone could not improve the above indices (all P > 0.05). Compared with medical treatment alone, low-dose PE combined with DPMAS/HP could reduce the short-term mortality rate of ACLF patients, especially the short-term mortality rate of ACLF patients with early-stage, early-middle-stage or type A ACLF, and there were significant differences between the two groups (all P < 0.05). In the low-dose PE+DPMAS/HP group, the patients with early-stage ACLF had significantly lower short- and long-term mortality rates than those with late-stage ACLF, and the patients with type A ACLF had significantly lower short- and long-term mortality rates than those with type C ACLF (all P < 0.05).Conclusion Low-dose PE combined with DPMAS/HP has good clinical efficacy and can effectively reduce the short-term mortality rate of ACLF, especially the short-term mortality rate of patients with early-stage, early-middle-stage, or type A ACLF.
按照UDCA治疗应答情况,637例患者中436例发生完全应答,201例为应答不良。性别分布中,完全应答组与应答不良组分布无统计学意义(P值均>0.05),基线存在肝硬化的患者UDCA应答率更高(78.9% vs 71.1%,P=0.032),生化指标中,TBil、AST、ALP、TBA和TC在两组间存在统计学差异(P值均<0.001)。免疫指标中,应答不良组IgA、IgM水平及抗Gp210阳性率均较高(P值均<0.05)。预后风险评分中,应答不良组MRS、Globe评分、UK-PBC评分均高于完全应答组(P值均<0.001)(表 2)。
表
2
UDCA治疗完全应答与应答不良患者基线指标及风险评分差异
Table
2.
Differences of baseline characteristics and risk scores between PBC with complete response and poor response to UDCA treatment
根据IgM预测UDCA应答不良的最佳临界值将患者分为IgM≥1.5×ULN及IgM<1.5×ULN两组,性别分布、年龄、肝硬化占比在两组中比较差异均无统计学意义(P值均>0.05);IgM≥1.5×ULN组AST、ALP、TC显著高于IgM<1.5×ULN组(P值均<0.05);IgM≥1.5×ULN组IgG水平及抗Gp210阳性率显著高于IgM<1.5×ULN组(P值均<0.001)。IgM≥1.5×ULN组经过UDCA治疗后发生应答不良患者显著高于IgM<1.5×ULN组(38.3% vs 27.1%,P=0.003)(表 5)。
表
5
不同IgM水平PBC患者基线临床特征及UDCA疗效比较
Table
5.
Comparison of baseline characteristics and the outcome of UDCA treatment between PBC with different levels of IgM
UDCA是PBC治疗的一线药物,可显著改善部分PBC患者非肝移植存活率[11-12],但仍有30%~40%的患者对UDCA治疗无应答,本研究中显示UDCA完全应答率为68.4%,对于这部分患者需要及时联合一种或两种二线药物来改善胆汁淤积以预防疾病进展[13]。UDCA治疗可能影响IgM水平,研究[14]发现UDCA能够显著降低细菌CpG诱导的总IgM和IgM-AMA的产生,但对IgG-AMA的水平却无影响。IgM与肝硬化相关症状和肝脏相关事件的发生关系密切,在UDCA联合苯扎贝特治疗过程中,不论ALP及GGT下降与否,当IgM水平持续异常时,患者的预后均较差,其生存期显著低于IgM水平正常化的患者,治疗过程中IgM水平的逐步正常化可能提示预后较好[15]。对于UDCA不完全应答的PBC患者,在给予联合利妥昔单抗治疗后,IgM水平随着肝功能指标的好转而逐步下降[16]。IgM正常化可作为长期预后的预测指标,但初始IgM正常患者IgM水平的变化情况及预测因素尚缺乏研究。在本研究中,UDCA治疗基线IgM平均水平为2.76 g/L,IgM升高的占比为56.0%,在UDCA完全应答组与应答不良组之间,基线IgM水平存在显著性差异(P=0.034),进一步分析IgM升高与IgM正常组患者的临床特征及在UDCA治疗1年后的疗效差异,发现IgM正常组UDCA应答率高于IgM升高组(71.8% vs 65.8%),但两组差异无统计学意义(P=0.108),通过ROC曲线分析获得IgM预测UDCA治疗1年后应答不良风险的最佳临界值(1.5×ULN),按最佳临界值进行分组后,结果显示IgM<1.5×ULN组的PBC患者发生UDCA应答率显著高于IgM≥1.5×ULN组(72.9% vs 61.7%, P=0.003),IgM≥1.5×ULN组发生UDCA应答不良风险是前者的1.416倍(95%CI: 1.129~1.776),因此基线IgM水平可能有助于预测PBC治疗应答。
HERNAEZ R, SOLÀ E, MOREAU R, et al. Acute-on-chronic liver failure: an update[J]. Gut, 2017, 66(3): 541-553. DOI: 10.1136/gutjnl-2016-312670.
[2]
ZHANG XL. Clinical study of combined non-biological artificial liver technology in the treatment of liver failure under the condition of blood stress[D]. Kunming: Kunming Medical University, 2018.
ZHANG XL, DUAN ZW, YANG RD, et al. Clinical study of plasma exchange combined with dual plasma molecular adsorption system in the treatment of patients with early and mid-stage liver failure under the condition of blood stress[J]. J Prac Hepatol, 2019, 22(2): 289-290. DOI: 10.3969/j.issn.1672-5069.2019.02.034.
Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Guideline for diagnosis and treatment of liver failure(2018)[J]. J Clin Hepatol, 2019, 35(1): 38-44. DOI: 10.3969/j.issn.1001-5256.2019.01.007.
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.
FAN Q, LI Z, Liver transplantation for chronic acute liver failure[J]. Qgran Transplant, 2022, 13(3): 333-337. DOI: 10.3969/j.issn.1674-7445.2022.03.008.
SUN KY, MAO JX, LIU Y, et al. Influencing factors of curative effect of plasma exchange in patients with HBV-related acute-on-chronic liver failure waiting for liver transplantation[J/CD]. Chin J Hepat Surg(Electronic Edition), 2022, 11(3): 252-257. DOI: 10.3877/cma.j.issn.2095-3232.2022.03.008.
LARSEN FS, SCHMIDT LE, BERNSMEIER C, et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial[J]. J Hepatol, 2016, 64(1): 69-78. DOI: 10.1016/j.jhep.2015.08.018.
[9]
YUAN S, QIAN Y, TAN D, et al. Therapeutic plasma exchange: A prospective randomized trial to evaluate 2 strategies in patients with liver failure[J]. Transfus Apher Sci, 2018, 57(2): 253-258. DOI: 10.1016/j.transci.2018.02.001.
[10]
BJURSTEN LM, RASMUSSON L, OH S, et al. Titanium dioxide nanotubes enhance bone bonding in vivo[J]. J Biomed Mater Res A, 2010, 92(3): 1218-1224. DOI: 10.1002/jbm.a.32463.
[11]
YAO J, LI S, ZHOU L, et al. Therapeutic effect of double plasma molecular adsorption system and sequential half-dose plasma exchange in patients with HBV-related acute-on- chronic liver failure[J]. J Clin Apher, 2019, 34(4): 392-398. DOI: 10.1002/jca.21690.
[12]
SUN J, GUO H, YU X, et al. A neutrophil-to-lymphocyte ratio-based prognostic model to predict mortality in patients with HBV-related acute-on-chronic liver failure[J]. BMC Gastroenterol, 2021, 21(1): 422. DOI: 10.1186/s12876-021-02007-w.
[13]
CHIRIAC S, STANCIU C, SINGEAP AM, et al. Prognostic value of neutrophil-to-lymphocyte ratio in cirrhotic patients with acute-on-chronic liver failure[J]. Turk J Gastroenterol, 2020, 31(12): 868-876. DOI: 10.5152/tjg.2020.19838.
[14]
JIE Y, GONG J, XIAO C, et al. Low platelet to white blood cell ratio indicates poor prognosis for acute-on-chronic liver failure[J]. Biomed Res Int, 2018, 2018: 7394904. DOI: 10.1155/2018/7394904.
[15]
YANG L, WU T, LI J, et al. Artificial liver treatment improves survival in patients with hepatitis B virus-related acute-on-chronic liver failure: A case-control matched analysis[J]. Hepatol Res, 2020, 50(6): 656-670. DOI: 10.1111/hepr.13497.
[16]
LIU H, ZHANG Q, LIU L, et al. Effect of artificial liver support system on short-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure[J]. Artif Organs, 2020, 44(10): E434-E447. DOI: 10.1111/aor.13710.
[17]
GUO X, WU F, GUO W, et al. Comparison of plasma exchange, double plasma molecular adsorption system, and their combination in treating acute-on-chronic liver failure[J]. J Int Med Res, 2020, 48(6): 300060520932053. DOI: 10.1177/0300060520932053.
[18]
CHEN JJ, HUANG JR, YANG Q, et al. Plasma exchange-centered artificial liver support system in hepatitis B virus-related acute-on-chronic liver failure: a nationwide prospective multicenter study in China[J]. Hepatobiliary Pancreat Dis Int, 2016, 15(3): 275-281. DOI: 10.1016/s1499-3872(16)60084-x.
[19]
CHEN YY, LI H, XU BY, et al. Plasma exchange-based non-bioartificial liver support system improves the short-term outcomes of patients with hepatitis B virus-associated acute-on-chronic liver failure: A multicenter prospective cohort study[J]. Front Med (Lausanne), 2021, 8: 779744. DOI: 10.3389/fmed.2021.779744.
[20]
TAN ZQ. Analysis of risk factors for the prognosis of patients with hepatitis B-related acute-on-chronic liver failure[D]. Nanchang: Nanchang University, 2021.
HAN L, LIANG QS, XIE H, et al. Value of baseline IgM level in predicting the treatment response of primary biliary cholangitis[J]. J Clin Hepatol, 2022, 38(4): 815-820. DOI: 10.3969/j.issn.1001-5256.2022.04.015.
HAN L, LIANG QS, XIE H, et al. Value of baseline IgM level in predicting the treatment response of primary biliary cholangitis[J]. J Clin Hepatol, 2022, 38(4): 815-820. DOI: 10.3969/j.issn.1001-5256.2022.04.015.