摘要
目前,有多种评估系统可用于肝癌预后指标的评估,均有各自的优势和局限性,而联合评估可能提高预测效能。因此,本研究探讨由年龄校正的查尔森合并症指数(aCCI)、肿瘤负荷评分(TBS)和白蛋白-胆红素(ALBI)评分构建的整合了合并症情况、形态学特征、肝功能的联合评分(aCTA评分)对肝癌肝切除术后肝功能衰竭(PHLF)的预测价值。
回顾性收集武汉大学人民医院2020年1月—2023年2月236例行肝切除术的原发性肝癌患者的临床资料。根据患者术后1周是否出现肝功能衰竭,分为PHLF组(19例)和非PHLF组(217例)。通过单变量分析和多变量Logistic回归筛选PHLF的独立危险因素,并以受试者工作特征(ROC)曲线评估联合指标的预测效能。通过Framingham研究中心Logistic模型建立积分系统的方法构建PHLF的加权风险评分。采用一致性指数(C指数)、ROC曲线和校准曲线进行内部验证;采用决策曲线分析(DCA)评价该评分的临床实用性。
236例肝癌肝切除患者中19例(8.1%)发生PHLF。Logistc多变量分析结果显示,aCCI(OR=1.557,95% CI=1.014~2.391,P=0.043)、TBS(OR=1.214,95% CI=1.022~1.442,P=0.027)、ALBI(OR=5.387,95% CI=1.844~15.733,P=0.002)是肝癌患者PHLF的独立危险因素(均P<0.05)。aCCI、TBS、ALBI及三者联合预测PHLF的ROC曲线下面积(AUC)分别是0.662、0.733、0.768、0.822。以aCCI、TBS、ALBI为基础,联合构建的aCTA评分系统(最高分为10分)的C指数为0.828(95% CI=0.732~0.925);AUC为0.809(P<0.05),表明该评分的区分度较好。该评分的校准曲线显示预测值与实际观测值接近,表明该评分预测的准确度较好;DCA显示,患者均能从aCTA评分模型中产生净收益,表明该评分具有良好的临床应用价值。
肝癌是全球发病率第6位,病死率第3位的常见恶性肿瘤,70%以上为肝细胞癌,发病率约为10/100 000
回顾性收集2020年1月—2023年2月期间武汉大学人民医院肝胆外科行原发性肝癌肝切除患者的临床资料。纳入标准:⑴ 病理诊断为原发性肝癌且临床资料完整;⑵ 年龄>18岁;⑶ 首次行肝切除术患者;⑷ 肝功能Child-Pugh分级A或B级且无远处转移。排除标准:⑴ 肝癌复发患者;⑵ 围手术期死亡患者;⑶ 行二步肝切除术、联合其他器官的肝癌患者;⑷ 资料不完整者。
目前对于肝癌肝切除患者PHLF的诊断尚无统一的标准。主要包括“50-50标准
患者性别、年龄、既往史(糖尿病、乙肝、肝硬化)、肿瘤数目、肿瘤大小、微血管侵犯(microvascular invasion,MVI)、Edmondson分级、吲哚菁绿15 min潴留率(ICG-R15)、aCCI、TBS、肝功能Child-Pugh评分、ALBI、BCLC分期、TNM分期、甲胎蛋白(alpha-fetoprotein,AFP)、丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartate transaminase,AST)、总胆红素(total bilirubin,TBIL)、血清白蛋白(albumin,ALB)、凝血酶原时间(prothrombin time,PT)、血小板(platelet,PLT)、血肌酐(serum creatinine,SCr)、总胆固醇、乳酸脱氢酶(lactate dehydrogenase,LDH)、美国麻醉医师协会(American Society of Anesthesiologists,ASA)分级、手术时间、肝门阻断时间、术中失血量、总住院时间等。
⑴ aCCI=共患疾病评分+对应年龄分组评分。对于伴有心肌梗死、充血性心力衰竭、周围血管病、痴呆、脑血管疾病、结缔组织疾病、消化性溃疡疾病、糖尿病、慢性肺病、轻度肝病的患者计1分:对伴有偏瘫、中度至重度慢性肾脏病、终末期糖尿病、实体瘤、白血病、淋巴瘤患者计2分:对伴有中重度肝脏疾病患者计3分:对于发生转移的肿瘤和艾滋病患者计6分;年龄<50岁计0分,50~59岁计1分,60~69岁计2分,70~79岁计3分,≥80岁计4分;⑵ TBS=;⑶ ALBI=0.66×log10[胆红素(μmol/L)]-0.085×白蛋白(g/L);ALBI分为3级,≤-2.60分为1级,>-2.6~-1.39分为2级,>-1.39分为3级。
采用SPSS 26.0统计软件进行分析。正态分布的计量资料以均数±标准差()表示,两两比较采用t检验;非正态分布的计量资料用中位数和四分位数间距[M(IQR)]表示,两组间的比较使用Mann-Whitney U检验。计数资料用频数和率表示,组间比较采用
比较肝癌患者PHLF和非PHLF的临床资料,筛选PHLF的影响因素。两者在aCCI、TBS、ALBI评分、ALT、AST、TBIL、肝段切除范围、总住院时间方面的差异有统计学意义(均P<0.05),其他变量差异无统计学意义(均P>0.05)(
变量 | PHLF组(n=19) | 非PHLF组(n=217) | P | |
---|---|---|---|---|
年龄[岁,n(%)] | ||||
<60 | 6(31.58) | 110(50.69) | 2.005 | 0.157 |
≥60 | 13(68.42) | 107(49.31) | ||
性别[n(%)] | ||||
男 | 14(73.68) | 169(77.88) | 0.177 | 0.647 |
女 | 5(26.32) | 48(22.12) | ||
糖尿病[n(%)] | 4(21.05) | 35(16.13) | 0.307 | 0.580 |
乙型肝炎[n(%)] | 13(68.42) | 139(64.06) | 0.145 | 0.703 |
肝硬化[n(%)] | 12(63.16) | 99(45.62) | 2.156 | 0.142 |
肿瘤数目[n(%)] | ||||
单发 | 12(63.16) | 156(71.89) | 0.649 | 0.420 |
多发 | 7(36.84) | 61(28.11) | ||
肿瘤直径[cm,n(%)] | ||||
>5 | 14(73.68) | 127(58.53) | 1.669 | 0.196 |
≤5 | 5(26.32) | 90(41.47) | ||
MVI [n(%)] | 10(52.63) | 78(35.94) | 2.080 | 0.149 |
Edmondson分级[n(%)] | ||||
1~2级 | 12(63.16) | 169(77.88) | 2.119 | 0.146 |
3~4级 | 7(36.84) | 48(22.12) | ||
ICG-R15 [%,M(IQR)] | 10(8~13.2) | 9.6(7.6~12) | -0.743 | 0.457 |
aCCI [M(IQR)] | 7(6~8) | 6(5~6) | -2.375 | 0.017 |
TBS [M(IQR)] | 7.6(4.6~9.9) | 5.1(3.6~7.1) | -3.262 | 0.001 |
肝功能Child-Pugh分级[n(%)] | ||||
A级 | 11(57.89) | 163(75.11) | 2.675 | 0.102 |
B级 | 8(42.11) | 54(24.89) | ||
ALBI评分[M(IQR)] | -2.23(-2.48~-1.611) | -2.62(-2.84~-2.38) | -3.874 | 0.001 |
BCLC分期[n(%)] | ||||
0~A期 | 11(57.89) | 145(66.82) | 0.621 | 0.431 |
B~C期 | 8(42.11) | 72(33.18) | ||
TNM分期[n(%)] | ||||
1~2期 | 10(52.63) | 157(72.35) | 3.283 | 0.070 |
3~4期 | 9(47.37) | 60(27.65) | ||
AFP [ng/mL,n(%)] | ||||
≥20 | 9(47.37) | 97(44.70) | 0.050 | 0.823 |
<20 | 10(52.63) | 120(55.30) |
变量 | PHLF组(n=19) | 非PHLF组(n=217) | P | |
---|---|---|---|---|
ALT [U/L,M(IQR)] | 37(23~64) | 25(16~39) | -2.508 | 0.012 |
AST [U/L,M(IQR)] | 37(29~63) | 28(21~39.5) | -2.603 | 0.009 |
TBIL [μmol/L,M(IQR)] | 55(26.4~108) | 14.5(11~19.3) | -5.509 | 0.001 |
ALB [g/L,M(IQR)] | 38.4(35.2~42.3) | 40(37~42.65) | -1.088 | 0.276 |
PT [s,M(IQR)] | 12(11.3~12.5) | 11.6(11~12.4) | -1.448 | 0.148 |
PLT [mg/L,M(IQR)] | 135(117~190) | 169(117~218) | -0.922 | 0.357 |
SCr [μmol/L,M(IQR)] | 67(60~83) | 64(55~75) | -1.457 | 0.145 |
总胆固醇[mmol/L,M(IQR)] | 3.82(3.03~5.61) | 3.98(3.4~4.535) | -0.109 | 0.913 |
LDH [U/L,M(IQR)] | 218(196~255) | 208(178~242) | -1.519 | 0.129 |
ASA分级[n(%)] | ||||
1~2级 | 10(52.63) | 123(56.68) | 0.105 | 0.746 |
3~4级 | 9(47.37) | 94(43.31) | ||
手术部位[n(%)] | ||||
左侧 | 8(42.11) | 63(29.03) | 1.970 | 0.373 |
右侧 | 10(52.63) | 125(57.61) | ||
双侧 | 1(5.26) | 29(13.36) | ||
肝段切除[n(%)] | ||||
≥3段 | 10(52.63) | 64(29.49) | 4.346 | 0.037 |
<3段 | 9(47.37) | 153(70.51) | ||
手术方式[n(%)] | ||||
开腹 | 9(47.37) | 114(52.53) | 0.187 | 0.666 |
腹腔镜 | 10(52.63) | 103(47.47) | ||
手术时间[h,n(%)] | ||||
>4 | 13(68.42) | 116(53.46) | 1.579 | 0.209 |
≤4 | 6(31.58) | 101(46.54) | ||
术中出血量[mL,n(%)] | ||||
>400 | 15(78.95) | 134(61.75) | 2.220 | 0.136 |
≤400 | 4(21.05) | 83(38.25) | ||
肝门阻断时间[min,M(IQR)] | 30(20~50) | 30(20~45) | -0.757 | 0.449 |
总住院时间[d,M(IQR)] | 20(17~26) | 18(14~23) | -2.160 | 0.031 |
变量 | β | SE | Wald/ | OR | 95% CI | P |
---|---|---|---|---|---|---|
aCCI | 0.443 | 0.219 | 4.101 | 1.557 | 1.014~2.391 | 0.043 |
TBS | 0.194 | 0.088 | 4.890 | 1.214 | 1.022~1.442 | 0.027 |
ALBI | 1.684 | 0.547 | 9.482 | 5.387 | 1.844~15.733 | 0.002 |
ALT | 0.003 | 0.005 | 0.317 | 1.003 | 0.993~1.014 | 0.574 |
AST | -0.002 | 0.007 | 0.083 | 0.998 | 0.984~1.012 | 0.773 |
肝段切除范围 | -0.173 | 0.579 | 0.089 | 0.842 | 0.271~2.616 | 0.766 |
总住院时间 | 0.029 | 0.039 | 0.557 | 1.030 | 0.953~1.112 | 0.455 |
aCCI、TBS、ALBI以及aCCI+TBS+ALBI三者联合的ROC曲线下面积(AUC)分别是0.662、0.733、0.768、0.822(

图1 aCCI、TBS、ALBI预测肝癌患者PHLF的ROC曲线
Figure 1 ROC curves of aCCI, TBS and ALBI to predict PHLF in patients with liver cancer
指标 | AUC | SE | 95% CI | P | 截断值 | 敏感度 | 特异度 | Youden指数 |
---|---|---|---|---|---|---|---|---|
aCCI | 0.662 | 0.058 | 0.548~0.775 | 0.020 | 6.50 | 0.895 | 0.392 | 0.286 |
TBS | 0.733 | 0.055 | 0.626~0.841 | 0.001 | 7.11 | 0.632 | 0.760 | 0.392 |
ALBI | 0.768 | 0.060 | 0.651~0.885 | 0.001 | -2.48 | 0.789 | 0.682 | 0.472 |
联合 | 0.822 | 0.050 | 0.723~0.921 | 0.001 | 0.07 | 0.789 | 0.756 | 0.545 |
本研究采取Framingham研究中心Logistic模型建立积分系统的方法,以TBS每增加5单位计为1分,此时常数为1.005,以此为基础计算aCCI、TBS、ALBI各分类所对应的分值,建立肝癌患者PHLF风险预测模型,该预测模型最高分为10分,分值越高,风险越高(
危险因素 | 得分 |
---|---|
aCCI | |
≤5 | 0 |
5~10 | 2 |
≥10 | 4 |
TBS | |
<5 | 0 |
5~10 | 1 |
>10 | 2 |
ALBI | |
≤-2.6 | 0 |
-2.6~-1.39 | 2 |
≥-1.39 | 4 |
运用bootstrap法(抽样1 000次)对该预测模型进行内部验证,其C指数为0.828(95% CI=0.732~0.925)。AUC为0.809(P<0.05),表明该评分的区分度较好(

图2 aCTA评分的验证 A:ROC曲线;B:校准曲线;C:DCA曲线
Figure 2 Validation of the aCTA score A: ROC curve; B: Calibration curve; C: DCA curve
项目 | 低风险组(n=169) | 高风险组(n=67) | Z/ | P |
---|---|---|---|---|
PHLF[n(%)] | 5(3.0) | 14(20.9) | 20.852 | 0.001 |
总住院时间[d,M(IQR)] | 17(13~21) | 20(16~25) | 3.610 | 0.001 |
目前,外科手术切除仍是治疗肝癌最有效的方法,而PHLF将严重影响肝癌患者术后生
aCCI通过对年龄及合并症进行量化整合,可用于胃癌、结直肠癌、卵巢癌等恶性肿瘤围手术期并发症和预后生存的评
常规肝功能检查的转氨酶、胆红素指标在单变量分析中有统计学意义,但并非独立危险因素,可能原因是单一指标判断肝功能较为片面,易受到多种因素的影响。随着肝癌患者的增多和手术技术提升,行半肝或三段以上肝切除患者增加,肝切除范围是PHLF的重要影响因
综上所述,aCCI、TBS、ALBI是肝癌患者PHLF的独立危险因素,以此建立的aCTA评分对高风险患者具有较好的预测价值和临床指导意义。
作者贡献声明
朱明强负责课题设计,资料分析,撰写论文;廖启成、李莹参与数据分析;谢星、王小华负责拟定写作思路并指导撰写论文;何晓、丁佑铭负责最后定稿。
利益冲突
本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
参考文献
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.21660. [百度学术]
Forner A, Reig M, Bruix J. Hepatocellular carcinoma[J]. Lancet, 2018, 391(10127):1301-1314. doi:10.1016/S0140-6736(18)30010-2. [百度学术]
van Mierlo KMC, Schaap FG, Dejong CHC, et al. Liver resection for cancer: new developments in prediction, prevention and management of postresectional liver failure[J]. J Hepatol, 2016, 65(6):1217-1231. doi: 10.1016/j.jhep.2016.06.006. [百度学术]
曾勇超, 丁宏达, 邹若媱, 等. 肝切除术后肝功能衰竭危险因素与防治的研究进展[J]. 中华肝胆外科杂志, 2019, 25(9):711-715. doi:10.3760/cma.j.issn.1007-8118.2019.09.020. [百度学术]
Zeng YC, Ding HD, Zou RY, et al. Research progress on the risk factors, prevention and therapy in posthepatectomy liver failure[J]. Chinese Journal of Hepatobiliary Surgery, 2019, 25(9):711-715. doi:10.3760/cma.j.issn.1007-8118.2019.09.020. [百度学术]
Okamura Y, Takeda S, Fujii T, et al. Prognostic significance of postoperative complications after hepatectomy for hepatocellular carcinoma[J]. J Surg Oncol, 2011, 104(7):814-821. doi: 10.1002/jso.21977. [百度学术]
Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade[J]. J Clin Oncol, 2015, 33(6):550-558. doi: 10.1200/JCO.2014.57.9151. [百度学术]
Rahbari NN, Reissfelder C, Koch M, et al. The predictive value of postoperative clinical risk scores for outcome after hepatic resection: a validation analysis in 807 patients[J]. Ann Surg Oncol, 2011, 18(13):3640-3649. doi: 10.1245/s10434-011-1829-6. [百度学术]
Wang YY, Zhong JH, Su ZY, et al. Albumin-bilirubin versus Child-Pugh score as a predictor of outcome after liver resection for hepatocellular carcinoma[J]. Br J Surg, 2016, 103(6):725-734. doi:10.1002/bjs.10095. [百度学术]
Yoshino K, Yoh T, Taura K, et al. A systematic review of prediction models for post-hepatectomy liver failure in patients undergoing liver surgery[J]. HPB (Oxford), 2021, 23(9):1311-1320. doi: 10.1016/j.hpb.2021.05.002. [百度学术]
Calthorpe L, Rashidian N, Cacciaguerra AB, et al. Using the Comprehensive Complication Index to Rethink the ISGLS Criteria for Post-hepatectomy Liver Failure in an International Cohort of Major Hepatectomies[J]. Ann Surg, 2023, 277(3):e592-596. doi: 10.1097/SLA.0000000000005338. [百度学术]
Zhong W, Zhang F, Huang K, et al. Development and Validation of a Nomogram Based on Noninvasive Liver Reserve and Fibrosis (PALBI and FIB-4) Model to Predict Posthepatectomy Liver Failure Grade B-C in Patients with Hepatocellular Carcinoma[J]. J Oncol, 2021, 2021:6665267. doi: 10.1155/2021/6665267. [百度学术]
薄飞, 王燕, 杜建文. 白蛋白-胆红素评分、吲哚箐绿15 min清除率与肝癌肝切除后发生肝衰的关系[J]. 中国普通外科杂志, 2020, 29(1):115-119. doi: 10.7659/j.issn.1005-6947.2020.01.014. [百度学术]
Bo F, Wang Y, Du JW. Relationship between albumin-bilirubin score, indocyanine green clearance rate for 15min and liver failure after hepatectomy for hepatocellular carcinoma[J]. China Journal of General Surgery, 2020, 29(1):115-119. doi: 10.7659/j.issn.1005-6947.2020.01.014. [百度学术]
谭学林, 王泽峰, 袁观斗, 等. 肝切除术后肝衰竭的预测模型研究进展[J]. 中华实验外科杂志, 2021, 38(8):1613-1616. doi:10.3760/cma.j.cn421213-20201215-01456. [百度学术]
Tan XL, Wang ZF, Yuan GD, et al. Research progress on prediction models of liver failure after hepatectomy[J]. Chinese Journal of Experimental Surgery, 2021, 38(8):1613-1616. doi: 10.3760/cma.j.cn421213-20201215-01456. [百度学术]
Søreide JA, Deshpande R. Post hepatectomy liver failure (PHLF) - Recent advances in prevention and clinical management[J]. Eur J Surg Oncol, 2021, 47(2):216-224. doi: 10.1016/j.ejso.2020.09.001. [百度学术]
Guo G, Lei Z, Tang X, et al. External Validation of Six Liver Functional Reserve Models to predict Posthepatectomy Liver Failure after Major Resection for Hepatocellular Carcinoma[J]. J Cancer, 2021, 12(17):5260-5267. doi:10.7150/jca.58726. [百度学术]
Kim KM, Shim SG, Sinn DH, et al. Child-Pugh, MELD, MELD-Na, and ALBI scores: which liver function models best predicts prognosis for HCC patient with ascites?[J]. Scand J Gastroenterol, 2020, 55(8):951-957. doi: 10.1080/00365521.2020.1788139. [百度学术]
Maezawa Y, Aoyama T, Kano K, et al. Impact of the Age-adjusted Charlson comorbidity index on the short- and long-term outcomes of patients undergoing curative gastrectomy for gastric cancer[J]. J Cancer, 2019, 10(22):5527-5535. doi: 10.7150/jca.35465. [百度学术]
Wu CC, Hsu TW, Chang CM, et al. Age-adjusted Charlson comorbidity index scores as predictor of survival in colorectal cancer patients who underwent surgical resection and chemoradiation[J]. Medicine, 2015, 94(2):e431. doi: 10.1097/MD.0000000000000431. [百度学术]
Kahl A, du Bois A, Harter P, et al. Prognostic value of the age-adjusted charlson comorbidity index (ACCI) on short- and long-term outcome in patients with advanced primary epithelial ovarian cancer[J]. Ann Surg Oncol, 2017, 24(12):3692-3699. doi: 10.1245/s10434-017-6079-9. [百度学术]
Alaimo L, Endo Y, Lima HA, et al. A comprehensive preoperative predictive score for post-hepatectomy liver failure after hepatocellular carcinoma resection based on patient comorbidities, tumor burden, and liver function: the CTF score[J]. J Gastrointest Surg, 2022, 26(12):2486-2495. doi: 10.1007/s11605-022-05451-5. [百度学术]
王祖凯, 林建贤, 许燕常, 等. 年龄调整的Charlson合并症指数影响腹腔镜胃癌根治术患者预后的多中心回顾性研究[J]. 中华消化外科杂志, 2022, 21(5):616-627. doi: 10.3760/cma.j.cn115610-20220403-00179. [百度学术]
Wang ZK, Lin JX, Xu YC, et al. Influences of age-adjusted Charlson comorbidity index on prognosis of patients undergoing laparoscopic radical gastrectomy: a multicenter retrospective study[J]. Chinese Journal of Digestive Surgery, 2022, 21(5):616-627. doi: 10.3760/cma.j.cn115610-20220403-00179. [百度学术]
Tsilimigras DI, Moris D, Hyer JM, et al. Hepatocellular carcinoma tumour burden score to stratify prognosis after resection[J]. Br J Surg, 2020, 107(7):854-864. doi: 10.1002/bjs.11464. [百度学术]
Wang JH, Chen ZG, Wang LH, et al. A new model based inflammatory index and tumor burden score (TBS) to predict the recurrence of hepatocellular carcinoma (HCC) after liver resection[J]. Sci Rep, 2022, 12:8670. doi: 10.1038/s41598-022-12518-5. [百度学术]
Hirokawa F, Hayashi M, Miyamoto Y, et al. Outcomes and predictors of microvascular invasion of solitary hepatocellular carcinoma[J]. Hepatol Res, 2014, 44(8):846-853. doi: 10.1111/hepr.12196. [百度学术]
Imura S, Teraoku H, Yoshikawa M, et al. Potential predictive factors for microvascular invasion in hepatocellular carcinoma classified within the Milan criteria[J]. Int J Clin Oncol, 2018, 23(1):98-103. doi: 10.1007/s10147-017-1189-8. [百度学术]
Na SK, Yim SY, Suh SJ, et al. ALBI versus Child-Pugh grading systems for liver function in patients with hepatocellular carcinoma[J]. J Surg Oncol, 2018, 117(5):912-921. doi: 10.1002/jso.24992. [百度学术]
Ho CHM, Chiang CL, Lee FAS, et al. Comparison of platelet-albumin-bilirubin (PALBI), albumin-bilirubin (ALBI), and child-pugh (CP) score for predicting of survival in advanced hcc patients receiving radiotherapy (RT)[J]. Oncotarget, 2018, 9(48):28818-28829. doi: 10.18632/oncotarget.25522. [百度学术]
Schindl MJ, Redhead DN, Fearon KH, et al. The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection[J]. Gut, 2005, 54(2):289-296. doi: 10.1136/gut.2004.046524. [百度学术]
Qadan M, Garden OJ, Corvera CU, et al. Management of Postoperative Hepatic Failure[J]. J Am Coll Surg, 2016, 222(2):195-208. doi:10.1016/j.jamcollsurg.2015.11.007. [百度学术]
Kim HJ, Kim CY, Park EK, et al. Volumetric analysis and indocyanine green retention rate at 15 min as predictors of post-hepatectomy liver failure[J]. HPB (Oxford), 2015, 17(2):159-167. doi: 10.1111/hpb.12295. [百度学术]