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

沈婷婷; 李光耀; 罗琼; 李盟; 孙鑫; 陶艳艳; 周祖山; 刘成海

doi:10.3969/j.issn.1001-5256.2022.09.022

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

沈婷婷¹,
李光耀²,
罗琼¹,
李盟¹,
孙鑫^{1, 3},
陶艳艳¹,
周祖山^2, , ,,
刘成海^{1, 3, , ,}

1.
上海中医药大学附属曙光医院肝病研究所，上海 201203
2.
湖北省洪湖市中医院风湿科，湖北洪湖 433220
3.
上海市中医临床重点实验室，上海 201203

基金项目:

上海市中医药事业发展三年行动计划 (ZY(2018-2020)-CCCX-5001);

上海市科学技术委员会科技计划项目 (20Z21900100);

上海市临床重点专科建设项目 (shslczdzk01201)

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。

详细信息

通信作者:
周祖山, zzs4013@163.com

刘成海, chenghailiu@hotmail.com

作者说明：沈婷婷目前在上海交通大学医学院附属同仁医院工作

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出版历程
- 收稿日期: 2022-01-27
- 录用日期: 2022-02-28
- 出版日期: 2022-09-20

Clinical features of drug-induced liver injury due to Tripterygium wilfordii preparation and concomitant medications in patients with rheumatoid arthritis

Tingting SHEN¹,
Guangyao LI²,
Qiong LUO¹,
Meng LI¹,
Xin SUN^{1, 3},
Yanyan TAO¹,
Zushan ZHOU^{2
, ,
,},
Chenghai LIU^{1, 3
, ,
,}

1.
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
2.
Department of Rheumatism, Honghu Hospital of Traditional Chinese Medicine, Honghu, Hubei 433220, China
3.
Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China

Research funding:

Three-year Action Plan of Shanghai TCM Development (ZY(2018-2020)-CCCX-5001);

Science and Technology Planning Project of Shanghai Science and Technology Commission (20Z21900100);

Shanghai Key Specialty of Traditional Chinese Clinical Medicine (shslczdzk01201)

More Information

Corresponding author: ZHOU Zushan, zzs4013@163.com(ORCID: 0000-0003-4274-2347); LIU Chenghai, chenghailiu@hotmail.com(ORCID: 0000-0002-2033-0934)

摘要

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.
- Arthritis, Rheumatoid /
- Tripterygium /
- Chemical and Drug Induced Liver Injury

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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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