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255例肝穿刺证实的慢性药物性肝损伤患者预后的影响因素分析
DOI: 10.3969/j.issn.1001-5256.2022.06.022
伦理学声明：本研究方案于2021年9月27日经由解放军总医院第五医学中心伦理委员会审批，批号: KY-2021-9-15-1。
利益冲突声明：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。
作者贡献声明：王巧玲负责提出研究选题，实施研究过程，起草论文，修订论文，终审论文; 梁庆生和谢欢负责采集数据，调研整理文献; 黄昂和翟兴冉负责统计分析，设计论文框架; 邹正升和孙颖负责技术或材料支持、指导性支持。
Influencing factors for the prognosis of biopsy proven patients with chronic drug-induced liver injury: An analysis of 255 cases
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摘要:
目的 探讨成人慢性药物性肝损伤(DILI)患者预后的影响因素。 方法 选取2014年1月—2018年12月于解放军总医院第五医学中心经肝穿刺明确诊断为慢性DILI患者255例，根据2年后患者的肝功能水平分为未恢复组和恢复组。统计两组患者的年龄、性别、BMI、用药种类、DILI损伤分型、DILI损伤严重程度、合并基础疾病、实验室指标、肝组织学结果及2年预后等临床资料。正态分布的计量资料两组间比较采用t检验; 非正态分布的计量资料两组间比较采用Mann -Whitney U检验。计数资料两组间比较采用χ2检验。采用logistic单因素及多因素回归分析慢性DILI预后的独立影响因素。 结果 经过两年的随访，195例患者肝功能恢复(76.5%)，60例(23.5%)未恢复。两组患者在肝损伤类型(P=0.028)、合并糖尿病(P=0.048)比例以及肝组织纤维化程度(P＜0.001)的差异具有统计学意义，且未恢复组患者基线WBC、PLT、ALT、AST、GGT和总胆汁酸水平明显高于恢复组患者，ChE水平低于恢复组患者(P值均＜0.05)。将基线特征纳入单因素分析logistic回归，结果显示PLT、ALT、AST、ChE、肝纤维化程度分级对预后的影响具有统计学意义(P值均＜0.05)。上述变量的多因素logistic回归分析结果显示，PLT＜100×109/L(OR=3.592，95%CI: 1.128~11.438，P=0.003)、ALT＞2×ULN(OR=3.080，95%CI: 1.331~7.127，P=0.009)是慢性DILI预后的独立危险因素。 结论 当患者达慢性DILI诊断标准时，基线PLT＜100×109/L、ALT＞2×ULN作为独立危险因素，可以用于筛选出更易出现不良预后的患者。 -
关键词:
- 药物性肝损伤, 慢性 /
- 预后 /
- 危险因素
Abstract:Objective To investigate the influencing factors for the prognosis of adult patients with chronic drug-induced liver injury (DILI). Methods A total of 255 patients who were diagnosed with chronic DILI by liver biopsy in The Fifth Medical Center of Chinese PLA General Hospital from January 2014 to December 2018 were enrolled, and according to the liver function after 2 years, they were divided into non-recovery group and recovery group. The two groups were analyzed in terms of the clinical data including age, sex, body mass index, types of drugs used, type of DILI injury, severity of DILI injury, underlying diseases, laboratory markers, liver histology, and 2-year prognosis. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. Univariate and multivariate logistic regression analyses were used to investigate the independent risk factors for the prognosis of chronic DILI. Results After 2 years of follow-up, 195 patients (76.5%) achieved the recovery of liver function, while 60 patients (23.5%) did not achieve such recovery. There were significant differences between the two groups in the type of DILI injury (P=0.028), the proportion of patients with diabetes (P=0.048), and the degree of liver fibrosis (P < 0.001), and compared with the recovery group, the non-recovery group had significantly higher levels of baseline white blood cell count, platelet count (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase, and total bile acid and a significantly lower level of cholinesterase (ChE) (all P < 0.05). The baseline characteristics were included in the univariate logistic regression analysis, and the results showed that PLT, ALT, AST, ChE, and fibrosis degree were significantly associated with the prognosis of chronic DILI (all P < 0.05). The multivariate logistic regression analysis of the above variables showed that PLT < 100×109/L (odds ratio [OR]=3.592, 95% confidence interval [CI]: 1.128-11.438, P=0.003) and ALT > 2×upper limit of normal (ULN) (OR=3.080, 95%CI: 1.331-7.127, P=0.009) were independent risk factors for the prognosis of chronic DILI. Conclusion When patients meet the diagnostic criteria for chronic DILI, the independent risk factors PLT < 100×109/L and ALT > 2×ULN may be used to screen out the patients who are more likely to have poor prognosis. -
Key words:
- Drug-Induced Liver Injury, Chronic /
- Prognosis /
- Risk Factors
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注：非甾体类抗炎药除外对乙酰氨基酚; 抗感染药物除外抗结核。
图 1 255例慢性DILI患者的致肝损伤药物
Figure 1. Implicated drugs of 255 patients with chronic DILI
图 2 恢复组与未恢复组各类肝损药物的占比情况
Figure 2. Proportion of classification of implicated drugs in two groups
表 1 255例慢性DILI患者的人口统计学和临床特点
Table 1. Demographics and clinical features of 255 patients with chronic DILI
项目 总患者
(n=255)恢复组
(n=195)未恢复组
(n=60)统计值 P值 女性[例(%)] 181(71.0) 141(72.3) 40(66.7) χ2=0.709 0.400 年龄(岁) 48(41~55) 48(40~55) 49(42~55) U=5 585.5 0.596 BMI(kg/m2) 23.67(21.48~25.74) 23.72(21.40~25.80) 23.60(21.70~25.40) U=5 709.0 0.966 用药史[例(%)] χ2=4.418 0.110 中药1) 107(42.0) 82(42.1) 25(41.7) 西药 109(42.7) 88(45.1) 21(35.0) 混合使用 39(15.3) 25(12.8) 14(23.3) 临床分型[例(%)] χ2=7.152 0.028 肝细胞型 71(27.8) 57(29.2) 14(23.3) 胆汁淤积型 95(37.3) 64(32.8) 31(51.7) 混合型 89(34.9) 74(37.9) 15(25.0) DILI严重程度分级[例(%)] χ2=5.172 0.160 1级 201(78.8) 155(79.5) 46(76.7) 2级 24(9.4) 21(10.7) 3(5.0) 3级 8(3.1) 6(3.1) 2(3.3) 4级 22(8.6) 13(6.7) 9(15.0) 合并基础疾病[例(%)] 高血压 43(16.9) 35(17.9) 8(13.3) χ2=0.697 0.404 糖尿病 13(5.1) 7(3.6) 6(10.0) χ2=3.897 0.048 血脂异常 91(35.7) 65(33.3) 26(43.3) χ2=1.999 0.157 实验室指标 WBC(×109/L) 4.75(4.04~5.84) 4.87(4.16~5.91) 4.45(3.77~5.34) U=4 669.5 0.018 嗜酸性粒细胞(×109/L) 0.11(0.06~0.18) 0.10(0.06~0.18) 0.11(0.05~0.18) U=5 695.5 0.757 Hb(g/L) 131(122~142) 131(122~142) 130(119~143) U=5 682.5 0.737 PLT(×109/L) 190.0(151.0~243.0) 198.5(154.5~246.5) 165.5(136.0~213.5) U=4 549.5 0.009 INR 0.96(0.90~1.03) 0.95(0.90~1.01) 0.96(0.90~1.05) U=5 421.0 0.390 ALT(U/L) 121.0(73.0~254.0) 112.0(67.0~222.5) 160.0(93.5~303.7) U=4 654.0 0.017 AST(U/L) 111.0(58.0~216.0) 106.0(56.0~186.5) 139.5(66.0~281.5) U=4 840.5 0.043 ALP(U/L) 150.0(120.0~194.0) 148.0(117.5~191.0) 155.0(135.0~222.0) U=5 085.0 0.126 TBil(μmol/L) 16.7(11.6~36.5) 16.2(11.1~33.4) 17.3(13.5~49.7) U=5 095.5 0.131 GGT(U/L) 140.0(91.0~222.0) 133.0(77.5~193.5) 164.3(122.0~291.0) U=4 311.0 0.002 前白蛋白(mg/L) 160.0(114.0~208.0) 158.5(115.5~207.5) 168.5(112.5~211.5) U=5 810.5 0.937 ChE(U/L) 6136(5048~7294) 6466(5261~7472) 6435(5289~7346) U=3 800.0 ＜0.001 TBA(μmol/L) 10.0(6.0~33.0) 9.2(5.0~26.5) 12.9(7.0~44.0) U=4 729.0 0.025 IgG(g/L) 13.0(11.0~15.7) 13.0(10.9~15.5) 12.7(11.2~16.0) U=5 527.5 0.519 IgM(g/L) 1.02(0.65~1.45) 1.00(0.70~1.40) 1.20(0.70~1.60) U=5 470.5 0.447 抗核抗体[例(%)] 51(20.0) 39(20.0) 12(20.0) χ2=0.000 1.000 注：1)包括保健品。 
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表 2 255例慢性DILI患者的肝组织病理学结果
Table 2. Pathological features of 255 patients with chronic DILI
项目 总患者
(n=255)恢复组
(n=195)未恢复组
(n=60)χ2值 P值 炎症程度分级[例(%)] 3.883 0.384 G1 94(36.9) 77(39.5) 17(28.3) G2 98(38.4) 74(37.9) 24(40.0) G3 59(23.1) 42(21.5) 17(28.3) G4 4(1.6) 2(1.0) 2(3.3) 纤维化程度分级[例(%)] 21.573 ＜0.001 S1 128(50.2) 109(55.9) 19(31.7) S2 87(34.1) 62(31.8) 25(41.7) S3 30(11.8) 22(11.3) 8(13.3) S4 10(3.9) 2(1.0) 8(13.3)
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表 3 预后影响因素的logistic单因素回归分析
Table 3. Univariate logistic regression analysis of influencing factors of prognosis
变量 OR 95%CI P值 变量 OR 95%CI P值 女性 0.766 0.411~1.426 0.401 ALT 年龄 ≤2×ULN ≤60岁 ＞2×ULN 2.899 1.345~6.250 0.007 ＞60岁 1.029 0.391~2.707 0.953 AST BMI ≤5×ULN ≤24 kg/m2 ＞5×ULN 1.930 1.036~3.594 0.038 ＞24 kg/m2 1.003 0.561~1.794 0.992 ALP 用药史 ≤2×ULN 中药1) ＞2×ULN 1.859 0.657~5.258 0.243 西药 0.812 0.418~1.575 0.537 TBil 混合使用 1.375 0.644~2.937 0.411 ≤2×ULN 临床分型 ＞2×ULN 1.532 0.791~2.965 0.206 肝细胞型 GGT 非肝细胞型 1.357 0.692~2.661 0.374 ≤2.5×ULN DILI严重程度分级 ＞2.5×ULN 1.954 0.897~4.255 0.092 1~2级 ChE 3~4级 2.079 0.928~4.662 0.075 ＜5000 U/L 2.154 1.140~4.069 0.018 合并症 ≥5000 U/L 高血压 0.703 0.307~1.612 0.406 TBA 糖尿病 2.984 0.962~9.253 0.058 ≤4×ULN 血脂异常 1.529 0.847~2.762 0.159 ＞4×ULN 1.502 0.766~2.945 0.236 PLT 纤维化程度分级 ＜100×109/L 3.087 1.070~8.904 0.037 S1~S2 ≥100×109/L S3~S4 2.591 1.269~5.291 0.009 注：1)包括保健品。
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表 4 预后影响因素的logistic多因素回归分析
Table 4. Multivariate logistic regression analysis of influencing factors of prognosis
变量 OR 95%CI P值 PLT ＜100×109/L 3.592 1.128~11.438 0.003 ≥100×109/L ALT ≤2×ULN ＞2×ULN 3.080 1.331~7.127 0.009 AST ≤5×ULN ＞5×ULN 1.195 0.599~2.384 0.614 ChE ＜5000 U/L 1.647 0.816~3.325 0.164 ≥5000 U/L 纤维化程度分级 S1~S2 S3~S4 2.084 0.970~4.479 0.060
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