糖皮质激素治疗重症药物性肝损伤的效果分析

严微; 黄会芳

doi:10.3969/j.issn.1001-5256.2022.10.019

糖皮质激素治疗重症药物性肝损伤的效果分析

DOI: 10.3969/j.issn.1001-5256.2022.10.019

严微¹,
黄会芳^2, , ,

1.
山西医科大学第一临床医学院，太原 030001
2.
山西医科大学第一医院消化内科，太原 030001

基金项目:

山西省自然科学基金 (201901D111357)

伦理学声明：本研究方案经由山西医科大学第一医院伦理委员会审批，批号：[2022]伦审字(K026)号。

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：严微负责设计课题，收集数据，资料分析，撰写论文；黄会芳参与拟定写作思路，指导论文撰写并修改论文。

详细信息

通信作者:
黄会芳，shxhhf@126.com

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出版历程
- 收稿日期: 2022-07-30
- 录用日期: 2022-08-31
- 出版日期: 2022-10-20

Effect of glucocorticoid in the treatment of severe drug-induced liver injury

Wei YAN¹,
Huifang HUANG^{2
, ,
,}

1.
The First Clinical Medical College of Shanxi Medical University, Taiyuan 030001, China
2.
Department of Gastroenterology, The First Hospital of Shanxi Medical University, Taiyuan 030001, China

Research funding:

Natural Science Foundation of Shanxi Province (201901D111357)

More Information

Corresponding author: HUANG Huifang, shxhhf@126.com(ORCID: 0000-0001-8526-0976)

摘要

摘要: 目的探讨重症药物性肝损伤(DILI)患者应用糖皮质激素的治疗效果。方法回顾性分析2019年1月—2021年9月山西医科大学第一医院收治的重症DILI患者资料，统计人口特征、肝损伤药物、临床表现，比较使用糖皮质激素治疗患者(激素组)与未使用激素患者(对照组)的肝功能变化、疗效及不良反应。计量资料两组间比较采用独立样本t检验或Mann-Whitney U检验。计数资料组间比较采用χ²检验或Fisher精确检验。结果共纳入88例DILI患者，其中男33例，女55例，中位年龄49岁；对照组61例，激素组27例。临床分型以肝细胞损伤型为主；肝损伤药物中，中药和膳食补充剂最为常见。临床表现以黄疸、恶心、纳差居多，6例患者(6.82%，6/88)进展为4级DILI，其中激素组2例，对照组4例。激素组与对照组患者基线特征比较，AST、GGT、TBil及免疫指标阳性占比差异均有统计学意义(P值均＜0.05)。两组治疗3 d时TBil、INR及TBA下降率比较，差异均有统计学意义(P值均＜0.05)；治疗7 d时，两组ALT、GGT、INR和TBA下降率差异均有统计学意义(P值均＜0.05)。激素组治疗3 d(59.26% vs 29.51%，χ²=55.82，P=0.008)和治疗7 d(81.48% vs 29.51%，χ²=64.27，P＜0.001)的累计有效率均明显高于对照组。激素组中2例4级重症DILI患者治疗均无效，而因常规保肝治疗后肝酶下降但胆红素持续升高或降低不明显而加用激素的患者中93.75%治疗有效。结论中药及膳食补充剂是最常见的肝损伤药物。对于常规治疗后胆红素降低不理想的3级DILI患者短期内使用激素可获益。
- 化学性与药物性肝损伤 /
- 糖皮质激素类 /
- 治疗学
Abstract: Objective To investigate the therapeutic effect of glucocorticoid in patients with severe drug-induced liver injury (DILI). Methods A retrospective analysis was performed for the data of patients with severe DILI who were admitted to The First Hospital of Shanxi Medical University from January 2019 to September 2021, including demographic characteristics, drugs inducing liver injury, and clinical manifestations, and changes in liver function, treatment outcome, and adverse reactions were compared between the patients treated with glucocorticoid (glucocorticoid group) and those not treated with glucocorticoid (control group). The independent samples t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. Results A total of 88 patients with DILI were included in analysis, among whom there were 33 male patients and 55 female patients, with a median age of 49 years, and there were 61 patients in the control group and 27 patients in the glucocorticoid group. Hepatocellular injury type was the main clinical type, and traditional Chinese medicine and dietary supplements were the most common drugs inducing liver injury. Main clinical manifestations included jaundice, nausea, and poor appetite, and 6 patients (6/88, 6.82%) progressed to grade 4 DILI, with 2 patients in the glucocorticoid group and 4 in the control group. The comparison of baseline characteristics showed that there were significant differences between the glucocorticoid group and the control group in aspartate aminotransferase, gamma-glutamyl transpeptidase (GGT), total bilirubin (TBil), and the proportion of patients with positive immune indices (all P < 0.05). On day 3 of treatment, there were significant differences between the two groups in the reduction rates of TBil, international normalized ratio (INR), and total bile acid (TBA) (all P < 0.05); on day 7 of treatment, there were significant differences between the two groups in the reduction rates of alanine aminotransferase, GGT, INR, and TBA (all P < 0.05). Compared with the control group, the glucocorticoid group had a significantly higher cumulative response rate on days 3 and 7 of treatment (day 3: 59.26% vs 29.51%, χ²=55.82, P=0.008; day 7: 81.48% vs 29.51%, χ²=64.27, P < 0.001). In the glucocorticoid group, the 2 patients with grade 4 DILI showed no response, while treatment response was observed in 93.75% of the patients who were treated with glucocorticoid due to the reduction in liver enzymes and the persistent increase (or a lack of significant reduction) in bilirubin after conventional liver-protecting treatment. Conclusion Traditional Chinese medicine and dietary supplements are the most common drugs inducing liver injury, and short-term use of glucocorticoids may bring benefits to the patients with grade 3 DILI who fail to achieve a satisfactory reduction in bilirubin after conventional treatment.
- Chemical and Drug Induced Liver Injury /
- Glucocorticoids /
- Therapeutics

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表 1 激素组与对照组基线特征比较

Table 1. Comparison of baseline characteristics between hormone group and control group

项目	对照组(n=61)	激素组(n=27)	统计值	P值
年龄(岁)	51.34±12.44	50.52±13.95	t=0.27	0.936
男性[例(%)]	21(34.43)	12(44.44)	χ²=0.80	0.371
低蛋白血症[例(%)]	14(22.95)	5(18.52)	χ²=0.22	0.641
高脂血症[例(%)]	25(40.98)	7(25.93)	χ²=1.83	0.176
高血压[例(%)]	9(14.75)	4(14.81)	χ²=0.01	0.994
糖尿病[例(%)]	7(11.48)	3(11.11)	χ²=0.01	0.985
ALT(U/L)	518.00(207.50~928.50)	494.75(240.25~1 065.15)	Z=-1.56	0.123
AST(U/L)	478.00(209.50~712.50)	360.50(157.45~684.65)	Z=-1.90	0.035
TBil(μmol/L)	213.60(133.00~287.45)	240.50(163.08~305.88)	Z=-2.50	0.019
ALP(U/L)	136.00(119.00~210.50)	121.50(101.50~386.75)	Z=-0.22	0.823
GGT(U/L)	137.00(84.50~253.50)	124.50(77.50~446.70)	Z=-2.36	0.025
TBA(μmol/L)	202.00(101.75~278.60)	255.70(84.88~384.50)	Z=-0.94	0.335
INR	1.16(1.06~1.36)	1.27(0.99~1.68)	Z=-0.55	0.570
免疫指标阳性[例(%)]	30(49.18)	1(3.70)	χ²=16.96	＜0.001
急性肝衰竭[例(%)]	4(4.55)	2(7.41)		0.487

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表 2 短期内不同时间点各实验室指标及其下降率比较

Table 2. Comparison of laboratory indicators and their decline rates at different time points in a short period

指标	例数	治疗3 d	治疗3 d下降率	治疗7 d	治疗7 d下降率
ALT(U/L)
对照组	61	218.00(120.00~405.00)	25.88%(4.68%~35.10%)	199.50(104.00~344.00)	59.53%(55.22%~73.27%)
激素组	27	190.00(131.00~358.00)	36.60%(36.07%~51.58%)	396.00(248.00~556.50)	36.84%(5.99%~68.43%)
Z值		-0.83	-0.56	-0.49	-2.35
P值		0.406	0.570	0.624	0.002
AST(U/L)
对照组	61	132.00(78.00~302.00)	30.80%(15.96%~51.06)%	100.50(57.00~196.00)	59.44%(26.12%~78.73%)
激素组	27	150.50(72.50~183.50)	56.39%(31.66%~65.49%)	103.00(77.00~199.50)	49.68%(7.58%~83.39%)
Z值		-1.55	-0.72	-1.75	-1.38
P值		0.121	0.467	0.079	0.167
ALP(U/L)
对照组	61	146.00(75.00~301.00)	12.66%(-1.59%~70.23%)	137.00(94.00~240.00)	22.35%(-2.25%~32.88%)
激素组	27	116.50(98.25~182.50)	2.97%(-27.46%~3.43%)	115.00(99.00~122.50)	45.26%(0.67%~78.28%)
Z值		-0.74	-0.74	-0.49	-0.28
P值		0.459	0.459	0.624	0.773
GGT(U/L)
对照组	61	173.00(53.00~244.00)	24.27%(6.54%~32.31%)	106.00(58.00~151.00)	28.99%(4.27%~53.61%)
激素组	27	64.00(57.00~151.00)	-6.76%(-16.22%~16.07%)	148.00(104.00~250.00)	-2.95%(-73.93%~38.89%)
Z值		-1.38	-0.60	-0.12	-4.26
P值		0.166	0.546	0.900	＜0.001
TBil(μmol/L)
对照组	61	244.60(196.00~405.60)	-3.18%(-6.71%~4.09%)	195.05(91.60~249.60)	36.39%(5.22%~55.74%)
激素组	27	167.55(112.00~243.50)	33.57%(21.75%~36.16%)	192.40(137.70~196.10)	35.63%(25.28%~73.60%)
Z值		-1.35	-3.68	-0.66	-1.38
P值		0.175	＜0.001	0.506	0.166
INR
对照组	61	1.54(1.00~2.09)	-4.58%(-41.16%~5.40%)	1.17(1.01~1.50)	3.79%(-2.50%~8.60%)
激素组	27	1.23(1.16~1.42)	46.39%(26.09%~63.08%)	0.98(0.54~1.57)	33.26%(7.30%~39.76%)
Z值		-0.37	-2.24	-1.50	-2.30
P值		0.707	0.025	0.132	0.021
TBA(μmol/L)
对照组	61	259.50(219.00~302.40)	-5.51%(-41.55%~2.15%)	144.45(109.30~277.00)	42.60%(-4.37%~78.45%)
激素组	27	201.95(38.78~421.45)	-45.34%(-46.46%~-10.30%)	20.30(19.30~180.65)	82.43%(65.53%~92.58%)
Z值		-1.92	-2.35	-0.83	-2.67
P值		0.054	0.019	0.404	0.008

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参考文献(20)

[1]	Chinese Medical Association, Chinese Medical Journals Publishing House, Chinese Society of Gastroenterology, et al. Guideline for primary care of drug-induced liver injury (2019)[J]. Chin J Gen Pract, 2020, 19(10): 868-875. DOI: 10.3760/cma.j.cn114798-20200812-00900. 中华医学会, 中华医学会杂志社, 中华医学会消化病学分会, 等. 药物性肝损伤基层诊疗指南(2019年)[J]. 中华全科医师杂志, 2020, 19(10): 868-875. DOI: 10.3760/cma.j.cn114798-20200812-00900.
[2]	DEVARBHAVI H, DIERKHISING R, KREMERS WK, et al. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality[J]. Am J Gastroenterol, 2010, 105(11): 2396-2404. DOI: 10.1038/ajg.2010.287.
[3]	HU PF, XIE WF. Corticosteroid therapy in drug-induced liver injury: Pros and cons[J]. J Dig Dis, 2019, 20(3): 122-126. DOI: 10.1111/1751-2980.12697.
[4]	Drug-induced Liver Disease Study Group, Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the management of drug-induced liver injury[J]. J Clin Hepatol, 2015, 31(11): 1752-1769. DOI: 10.3969/j.issn.1001-5256.2015.11.002. 中华医学会肝病学分会药物性肝病学组. 药物性肝损伤诊治指南[J]. 临床肝胆病杂志, 2015, 31(11): 1752-1769. DOI: 10.3969/j.issn.1001-5256.2015.11.002.
[5]	LI WT, YANG L, HE HL, et al. Application of glucocorticosteroid in drug induced liver injury[J]. Chin Hepatol, 2020, 25(7): 676-678. https://www.cnki.com.cn/Article/CJFDTOTAL-ZUAN202007008.htm 李文庭, 杨亮, 何宏亮, 等. 药物性肝损伤糖皮质激素应用的时机与指征[J]. 肝脏, 2020, 25(7): 676-678. https://www.cnki.com.cn/Article/CJFDTOTAL-ZUAN202007008.htm
[6]	SGRO C, CLINARD F, OUAZIR K, et al. Incidence of drug-induced hepatic injuries: a French population-based study[J]. Hepatology, 2002, 36(2): 451-455. DOI: 10.1053/jhep.2002.34857.
[7]	BJÖRNSSON ES, BERGMANN OM, BJÖRNSSON HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland[J]. Gastroenterology, 2013, 144(7): 1419-1425. DOI: 10.1053/j.gastro.2013.02.006.
[8]	SHEN T, LIU Y, SHANG J, et al. Incidence and etiology of drug-induced liver injury in mainland China[J]. Gastroenterology, 2019, 156(8): 2230-2241. DOI: 10.1053/j.gastro.2019.02.002.
[9]	NAVARRO VJ, KHAN I, BJÖRNSSON E, et al. Liver injury from herbal and dietary supplements[J]. Hepatology, 2017, 65(1): 363-373. DOI: 10.1002/hep.28813.
[10]	European Association for the Study of the Liver. EASL clinical practice guidelines: Drug-induced liver injury[J]. J Hepatol, 2019, 70(6): 1222-1261. DOI: 10.1016/j.jhep.2019.02.014.
[11]	MOHAMMAD I, STARSKAIA I, NAGY T, et al. Estrogen receptor α contributes to T cell-mediated autoimmune inflammation by promoting T cell activation and proliferation[J]. Sci Signal, 2018, 11(526): eaap9415. DOI: 10.1126/scisignal.aap9415.
[12]	ROBLES-DIAZ M, GARCIA-CORTES M, MEDINA-CALIZ I, et al. The value of serum aspartate aminotransferase and gamma-glutamyl transpetidase as biomarkers in hepatotoxicity[J]. Liver Int, 2015, 35(11): 2474-2482. DOI: 10.1111/liv.12834.
[13]	LI X, XU H, GAO P. Increased red cell distribution width predicts severity of drug-induced liver injury: a retrospective study[J]. Sci Rep, 2021, 11(1): 773. DOI: 10.1038/s41598-020-80116-4.
[14]	YU YC, CHEN CW. Pathogenesis of drug-induced liver injury: Current understanding and future needs[J]. J Clin Hepatol, 2021, 37(11): 2515-2524. DOI: 10.3969/j.issn.1001-5256.2021.11.003. 于乐成, 陈成伟. 药物性肝损伤的发生机制: 当前认识和未来需求[J]. 临床肝胆病杂志, 2021, 37(11): 2515-2524. DOI: 10.3969/j.issn.1001-5256.2021.11.003.
[15]	FONTANA RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives[J]. Gastroenterology, 2014, 146(4): 914-928. DOI: 10.1053/j.gastro.2013.12.032.
[16]	PARK BK, LAVERTY H, SRIVASTAVA A, et al. Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity[J]. Chem Biol Interact, 2011, 192(1-2): 30-36. DOI: 10.1016/j.cbi.2010.09.011.
[17]	HU PF, WANG PQ, CHEN H, et al. Beneficial effect of corticosteroids for patients with severe drug-induced liver injury[J]. J Dig Dis, 2016, 17(9): 618-627. DOI: 10.1111/1751-2980.12383.
[18]	BJÖRNSSON HK, GUDBJORNSSON B, BJÖRNSSON ES. Infliximab-induced liver injury: Clinical phenotypes, autoimmunity and the role of corticosteroid treatment[J]. J Hepatol, 2022, 76(1): 86-92. DOI: 10.1016/j.jhep.2021.08.024.
[19]	KARKHANIS J, VERNA EC, CHANG MS, et al. Steroid use in acute liver failure[J]. Hepatology, 2014, 59(2): 612-21. DOI: 10.1002/hep.26678.
[20]	DONG JL, JIA L, YANG J, et al. Expression features of glucocorticoid receptor and its association with treatment outcome in patients with hepatitis B virus-related acute-on-chronic liver failure[J]. J Clin Hepatol, 2020, 36(6): 1252-1257. DOI: 10.3969/j.issn.1001-5256.2020.06.013. 董金玲, 贾琳, 杨君, 等. HBV相关慢加急性肝衰竭患者糖皮质激素受体表达特征及其与疗效的关系[J]. 临床肝胆病杂志, 2020, 36(6): 1252-1257. DOI: 10.3969/j.issn.1001-5256.2020.06.013.