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类风湿性关节炎患者应用雷公藤制剂及合并用药所致药物性肝损伤的临床特征分析
DOI: 10.3969/j.issn.1001-5256.2022.09.022
伦理学声明: 本研究方案于2018年8月经由上海中医药大学附属曙光医院伦理委员会审批，批号：2020-858-64-01，所有患者入组前均签署知情同意书。
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：沈婷婷负责课题设计，资料分析，撰写论文；李光耀、罗琼、李盟、孙鑫、陶艳艳参与收集数据，修改论文；周祖山、刘成海负责拟定写作思路，指导撰写文章并最后定稿。
Clinical features of drug-induced liver injury due to Tripterygium wilfordii preparation and concomitant medications in patients with rheumatoid arthritis
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摘要:
目的 观察分析类风湿性关节炎患者使用雷公藤制剂及合并用药发生药物性肝损伤(DILI)的临床特征。 方法 回顾性收集2014年1月—2019年12月于洪湖市中医院使用雷公藤制剂及合并用药所致DILI的112例类风湿性关节炎患者的临床资料，观察人口统计学资料及DILI的临床特征，并探讨合并用药和基础疾病对DILI的影响。计量资料多组间及进一步两两比较采用Kruskal-Wallis H检验。 结果 患者平均年龄为(48.13±14.38)岁，女性81例(72.32%)，在合并基础疾病中以非酒精性脂肪性肝病较为多见，共8例(7.14%)，在联合用药中以雷公藤制剂中药联合非甾体消炎药(NSAID)/抗风湿药物(DMARD)多见，共70例(62.50%)。患者主要临床表现为关节痛，共110例(98.21%)。102例(91.07%)为肝脏生化学检查异常；RUCAM评分为6~8分的患者有66例(58.93%)，110例(98.21%)为轻度肝损伤(1级)；通过保肝治疗(均＜6个月)，所有患者肝功能均好转，无加重及死亡。雷公藤制剂+糖皮质激素+NSAID/DMARD联用组(n=22)的血清ALP、GGT较雷公藤制剂+NSAID/DMARD联用组(n=70)显著升高(P值均＜0.05)。合并非酒精性脂肪性肝病组患者(n=8)较无基础疾病组(n=90)患者血清ALT升高更显著(P＜0.05)。 结论 类风湿性关节炎患者可因用雷公藤制剂及合并用药发生DILI，以中年女性居多，临床表现以关节痛为主，肝功能损伤较轻，无明显慢性化，预后较好。联合使用糖皮质激素和NSAID/DMARD的患者，或者合并非酒精性脂肪性肝病基础疾病的患者，肝损伤更严重。 -
关键词:
- 关节炎, 类风湿 /
- 雷公藤属 /
- 化学性与药物性肝损伤
Abstract:Objective To investigate the clinical features of drug-induced liver injury (DILI) due to Tripterygium wilfordii preparation and concomitant medications in patients with rheumatoid arthritis (RA). Methods A retrospective analysis was performed for the clinical data of 112 RA patients with DILI caused by Tripterygium wilfordii preparations and concomitant medications who were treated in Honghu Hospital of Traditional Chinese Medicine from January 2014 to December 2019, and demographic data and the clinical features of DILI were observed to explore the influence of concomitant medications and underlying diseases on DILI. The Kruskal-Wallis H test was used for comparison of continuous data between multiple groups and further comparison between two groups. Results All 112 patients had a mean age of 48.13±14.38 years, and there were 81 female patients (72.32%). The most common underlying disease was nonalcoholic fatty liver disease (NAFLD) in 8 patients (7.14%), and as for concomitant medications, 70 patients (62.50%) were treated with Tripterygium wilfordii preparation combined with non-steroid anti-inflammatory drug (NSAID) or disease-modifying anti-rheumatic drug (DMARD). The main clinical manifestation was joint pain in 110 patients (98.21%). Among the 112 patients, 102 (91.07%) had abnormal results of liver biochemical examinations; 66 patients (58.93%) had an RUCAM score of 6-8 points, and 110 patients (98.21%) had mild (grade 1) liver injury. After liver-protecting treatment (for less than 6 months in all patients), all patients had an improvement in liver function without aggravation or death. The Tripterygium wilfordii preparation+glucocorticoid+NSAID/DMARD group with 22 patients had significant increases in the serum levels of alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) compared with the Tripterygium wilfordii preparation+NSAID/DMARD group with 70 patients (P < 0.05). The 8 patients with NAFLD had a significantly greater increase in serum alanine aminotransferase compared with the 90 patients without underlying diseases (P < 0.05). Conclusion RA patients may develop DILI due to Tripterygium wilfordii preparation and concomitant medications, which is commonly observed in middle-aged women. Joint pain is the main clinical manifestation, and patients tend to have mild liver injury and good prognosis without marked chronicity. More severe liver injury is observed in patients with combined medication of glucocorticoids and NSAID/DMARD or those with the underlying disease of NAFLD. -
表 1 112例DILI患者的一般情况
Table 1. Baseline characteristics of 112 DILI patients
项目 例数及占比 年龄 ＜18岁 7(6.25) 18~40岁 19(16.96) 41~60岁 63(56.25) ＞60岁 23(20.54) 性别 男 31(27.68) 女 81(72.32) 饮酒史 2(1.79) 长期饮酒 1(0.89) 偶尔饮酒 1(0.89) 雷公藤制剂服用时间 7 d内 1(0.89) 7~90 d 32(28.57) 90~180 d 20(17.86) 180 d~1年 31(27.68) 1年以上 28(25.00) 合并肝胆系统疾病 12(10.71) 非酒精性脂肪性肝病 8(7.14) 胆囊结石 2(1.79) 肝内胆管结石 2(1.79) 合并高血压 7(6.25) 合并糖尿病 3(2.68) 合并免疫系统疾病 2(1.79) 干燥综合征 1(0.89) 甲状腺功能减退 1(0.89) 合并其他疾病 3(2.68) 肾结石 1(0.89) 肾积水 1(0.89) 乳腺肿瘤 1(0.89) 
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表 2 雷公藤制剂及合并用药情况
Table 2. Tripterygium preparations and concomitant drugs
合并用药归类 例数及占比 雷公藤制剂中药 10(8.93) 雷公藤制剂中药+糖皮质激素 10(8.93) 雷公藤制剂中药+NSAID/DMARD 70(62.50) 合并1种NSAID/DMARD 53(75.71) 合并2种NSAID/DMARD 14(20.00) 合并3种NSAID/DMARD 3(4.29) 雷公藤制剂中药+糖皮质激素+NSAID/DMARD 22(19.64)
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表 3 112例患者的临床表现、DILI临床分型、RUCAM评分及严重程度分级
Table 3. Clinical manifestations, DILI clinical classification, RUCAM score and severity classification of 112 patients
统计要素 例数及占比 临床表现 发热 3(2.68) 乏力 4(3.57) 口干/口苦 46(41.07) 呕吐/厌油 3(2.68) 胃纳减退 3(2.68) 便秘 3(2.68) 关节痛 110(98.21) DILI临床类型 肝细胞损伤型 5(4.46) 胆汁淤积型 5(4.46) 混合型 0 肝脏生化学异常 102(91.07) 雷公藤制剂RUCAM评分 3~5(可能) 16(14.29) 6~8(很可能) 66(58.93) ＞8(极可能) 30(26.79) DILI严重程度分级 1级(轻度肝损伤) 110(98.21) 2级(中度肝损伤) 2(1.79) 3级及以上 0
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表 4 雷公藤制剂及合并用药导致的DILI
Table 4. DILI caused by tripterygium wilfordii preparations and concomitant medications
项目 雷公藤制剂中药(n=10) 雷公藤制剂中药+ 糖皮质激素(n=10) 雷公藤制剂中药+ NSAID/DMARD (n=70) 雷公藤制剂中药+ 糖皮质激素+ NSAID/DMARD (n=22) H值 P值 肝功能 ALT(U/L) 64.00(56.00~76.25) 73.50(59.00~110.75) 75.50(63.50~114.75) 90.50(65.75~143.25) 5.664 0.129 AST(U/L) 39.50(33.75~47.00) 37.00(26.00~66.75) 57.50(41.00~73.00) 56.00(33.25~82.00) 8.107 0.044 ALP(U/L) 100.00(78.75~118.00) 100.00(90.54~130.02) 91.02(66.76~125.01) 155.02(89.75~261.28)1) 12.105 0.007 GGT(U/L) 59.45(40.55~88.00) 63.00(37.54~165.00) 37.85(22.65~70.10) 101.66(63.88~170.23)1) 17.139 0.001 TBil(μmol/L) 11.55(7.58~13.97) 7.50(4.14~11.98) 9.10(6.75~11.73) 8.45(6.38~10.50) 4.223 0.238 DBil(μmol/L) 2.55(2.02~3.50) 2.25(1.43~3.60) 2.40(1.80~3.40) 2.35(1.88~2.93) 1.007 0.800 Alb(g/L) 39.60(35.98~41.30) 37.00(32.90~38.33) 38.20(33.90~41.23) 36.05(34.48~37.10) 7.399 0.060 TBA(μmol/L) 4.55(3.45~7.33) 6.91(4.30~13.90) 4.55(2.75~8.18) 4.25(3.13~6.43) 2.068 0.558 DILI临床类型(例) 肝细胞损伤型 0 0 5 0 胆汁淤积型 0 1 2 2 混合型 0 0 0 0 肝脏生化学异常 10 9 63 20 DILI严重程度分级(例) 1级(轻度) 10 10 68 22 2级(中度) 0 0 2 0 3级及以上 0 0 0 0 注：与雷公藤制剂中药+NSAID/DMARD组比较，1)P＜0.05。
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表 5 患者合并基础疾病与雷公藤制剂及合并用药导致DILI的关系
Table 5. The relationship between underlying diseases and DILI caused by tripterygium wilfordii preparations and concomitant medications
项目 无合并基础疾病(n=90) 合并非酒精性脂肪性肝病(n=8) 合并高血压(n=7) H值 P值 肝功能 ALT(U/L) 74.50(61.75~109.75) 118.50(92.75~198.25)1) 68.00(60.00~147.00) 6.598 0.037 AST(U/L) 48.50(38.25~69.25) 52.50(40.00~66.50) 55.00(52.00~139.00) 1.628 0.443 ALP(U/L) 98.00(75.00~136.00) 124.50(65.00~249.00) 114.00(78.04~132.00) 0.569 0.752 GGT(U/L) 45.07(25.00~85.50) 70.80(50.08~123.40) 85.00(42.10~195.50) 5.077 0.079 TBil(μmol/L) 8.40(6.30~11.70) 11.20(9.83~12.78) 8.70(6.60~12.50) 4.424 0.110 DBil(μmol/L) 2.40(1.80~3.18) 2.75(2.35~3.70) 2.40(2.20~3.60) 2.639 0.267 Alb(g/L) 37.35(34.13~39.60) 41.05(36.98~45.48) 37.10(32.20~37.80) 6.052 0.049 TBA(μmol/L) 4.80(2.90~8.10) 5.45(2.00~6.78) 7.30(4.10~12.80) 2.542 0.280 DILI临床类型 肝细胞损伤型 3 1 0 混合型 0 0 0 肝脏生化学异常 83 6 7 DILI严重程度分级 1级(轻度) 89 7 7 2级(中度) 1 1 0 3级及以上 0 0 0 注：与无合并基础疾病组比较，1)P＜0.05。
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[1] 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. e11. DOI: 10.1053/j.gastro.2019.02.002. [2] ZHU CW, WANG HN, YUAN JL, et al. Clinical features of drug-induced liver injury: an analysis of 445 cases[J]. J Clin Hepatol, 2018, 34(2): 5. DOI: 10.3969/j.issn.1001-5256.2018.02.027.朱春雾, 王海南, 袁继丽, 等. 445例药物性肝损伤的临床分析[J]. 临床肝胆病杂志, 2018, 34(2): 5. DOI: 10.3969/j.issn.1001-5256.2018.02.027. [3] XU JM. A multicenter survey on hospital inpatients with drug-induced acute liver injury in China[J]. Chin J Dig, 2007, 27(7): 439-442. DOI: 10.3760/j.issn:0254-1432.2007.07.003.许建明. 全国多中心急性药物性肝损伤住院病例调研分析[J]. 中华消化杂志, 2007, 27(7): 439-442. DOI: 10.3760/j.issn:0254-1432.2007.07.003. [4] ZHU Y, NIU M, CHEN J, et al. Hepatobiliary and pancreatic: Comparison between Chinese herbal medicine and Western medicine-induced liver injury of 1985 patients[J]. J Gastroenterol Hepatol, 2016, 31(8): 1476-1482. DOI: 10.1111/jgh.13323. [5] ZHOU Y, YANG L, LIAO Z, et al. Epidemiology of drug-induced liver injury in China: a systematic analysis of the Chinese literature including 21, 789 patients[J]. Eur J Gastroenterol Hepatol, 2013, 25(7): 825-829. DOI: 10.1097/MEG.0b013e32835f6889. [6] LUO JL, WEI RN, YU TY, et al. Study on the clinical application and dosage of Tripterygium wilfordii[J]. J Changchun Univ Chin Med, 2022, 38(5): 491-494. DOI: 10.13463/j.cnki.cczyy.2022.05.006.罗金丽, 卫若楠, 于同月, 等. 雷公藤的临床应用及其用量探究[J]. 长春中医药大学学报, 2022, 38(5): 491-494. DOI: 10.13463/j.cnki.cczyy.2022.05.006. [7] LIU J, YAN LJ. Effects of triptolide on angiogenesis and PTEN/PI3K/AKT pathway in model rats with rheumatoid arthritis[J]. J Jilin Univ: Med Edit, 2020, 286(6): 1227-1233, 1351. DOI: 10.13481/j.1671-587x.20200619.刘静, 燕丽君. 雷公藤内酯醇对类风湿性关节炎模型大鼠血管新生和PTEN/PI3K/AKT通路的影响[J]. 吉林大学学报: 医学版, 2020, 286(6): 1227-1233, 1351. DOI: 10.13481/j.1671-587x.20200619. [8] ZHU CW, WANG HN, ZHANG YL, et al. Analysis of clinical characteristics in 140 patients with herb-induced liver injury[J]. Chin Hepatol, 2019, 24(4): 362-364. DOI: 10.3969/j.issn.1008-1704.2019.04.009.朱春雾, 王海南, 张亚蕾, 等. 140例中药肝损伤病例的临床特征分析[J]. 肝脏, 2019, 24(4): 362-364. DOI: 10.3969/j.issn.1008-1704.2019.04.009. [9] SONG D, GE FL, ZHANG L, et al. Analysis of liver injury associated with preparations containing tripterygium wilfordii[J]. Chin J Pharmacov, 2019, 16(5): 265-269. DOI: 10.3969/j.issn.1672-8629.2019.05.003.宋迪, 葛斐林, 张乐, 等. 雷公藤制剂相关肝损伤分析[J]. 中国药物警戒, 2019, 16(5): 265-269. DOI: 10.3969/j.issn.1672-8629.2019.05.003. [10] YANG T, ZHANG YL, ZHU TT, et al. A preliminary study on clinical characteristics and toxicology mechanism of tripterygium wilfordii induced liver injury[J]. World Sci Technol Modern Tradit Chin Med, 2018, 20(11): 2027-2032. DOI: 10.11842/wst.2018.11.021.杨涛, 张亚蕾, 朱亭亭, 等. 雷公藤致肝损伤的临床特点与主要机制[J]. 世界科学技术-中医药现代化, 2018, 20(11): 2027-2032. DOI: 10.11842/wst.2018.11.021. [11] Drug - induced Liver Disease Study Group. Chinese 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. [12] TODOROVIĆVUKOTIĆ N, ƉOR ƉEVIĆ J, et al. Antidepressants- and antipsychotics-induced hepatotoxicity[J]. Arch Toxicol, 2021, 95(3): 767-789. DOI: 10.1007/s00204-020-02963-4. [13] BENESIC A, JALAL K, GERBES AL. Drug-drug combinations can enhance toxicity as shown by monocyte-derived hepatocyte-like cells from patients with idiosyncratic drug-induced liver injury[J]. Toxicol Sci, 2019. DOI: 10.1093/toxsci/kfz156.[Online ahead of print] [14] MARTINEZ MA, VUPPALANCHI R, FONTANA RJ, et al. Clinical and histologic features of azithromycin-induced liver injury[J]. Clin Gastroenterol Hepatol, 2015, 13(2): 369-376. e3. DOI: 10.1016/j.cgh.2014.07.054. [15] DEVARBHAVI H, AITHAL G, TREEPRASERTSUK S, et al. Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines[J]. Hepatol Int, 2021, 15(2): 258-282. DOI: 10.1007/s12072-021-10144-3. [16] CHALASANI N, BONKOVSKY HL, FONTANA R, et al. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study[J]. Gastroenterology, 2015, 148(7): 1340-1352. e7. DOI: 10.1053/j.gastro.2015.03.006. [17] CHALASANI NP, HAYASHI PH, BONKOVSKY HL, et al. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury[J]. Am J Gastroenterol, 2014, 109(7): 950-966; quiz 967. DOI: 10.1038/ajg.2014.131. [18] FROMENTY B. Drug-induced liver injury in obesity[J]. J Hepatol, 2013, 58(4): 824-826. DOI: 10.1016/j.jhep.2012.12.018. [19] MICHAUT A, MOREAU C, ROBIN MA, et al. Acetaminophen-induced liver injury in obesity and nonalcoholic fatty liver disease[J]. Liver Int, 2014, 34(7): e171-e179. DOI: 10.1111/liv.12514. -
