中药利胆合剂调节氧化应激拮抗婴儿胆汁淤积性肝纤维化的临床观察

Effects of Li-Dan-He-Ji on regulating oxidative stress and antagonising infantile cholestatic hepatic fibrosis

目的探讨利胆合剂治疗胆汁淤积性肝纤维化患儿的临床效果。方法采用前瞻性随机对照研究方法,入选华中科技大学同济医学院附属武汉儿童医院中西医结合科和消化内科2021年1月至12月收治的符合婴儿胆汁淤积性肝纤维化诊断标准的患儿,按照随机数字表法分为常规治疗组和利胆合剂组。常规治疗组按照指南给予常规治疗;利胆合剂组在常规治疗组基础上给予自拟中药复方利胆合剂(组方:茵陈、连翘、熟大黄、制首乌、赤芍、桂枝、枳壳、白术、五味子、鳖甲、甘草)口服、灌肠或鼻饲治疗,每日60 mL,分2~3次给予,共治疗28 d,门诊随访4周。记录两组患者治疗前后血清肝纤维化4项〔Ⅳ型胶原(Ⅳ-C)、透明质酸酶(HA)、Ⅲ型前胶原(PCⅢ)、层黏连蛋白(LN)〕、肝功能及胆汁淤积相关标志物〔总胆红素(TBil)、直接胆红素(DBil)、总胆汁酸(TBA)、碱性磷酸酶(ALP)、γ-谷氨酰转肽酶(γ-GGT)、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)〕、氧化应激指标〔超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽(GSH)〕、瞬时弹性成像(TE)检测肝脏硬度值(LSM)、天冬氨酸转氨酶/血小板比值指数(APRI)以及肝脾回缩时间。结果观察期间共收治40例胆汁淤积性肝纤维化患儿,其中常规治疗组21例,利胆合剂组19例。两组治疗前血清肝纤维化4项、血清肝功能及胆汁淤积相关标志物、氧化应激指标、LSM及APRI比较差异均无统计学意义。两组治疗后肝纤维化4项、肝功能及胆汁淤积相关标志物、LSM、APRI均较治疗前显著下降,且利胆合剂组上述指标明显低于常规治疗组〔HA(ng/L):165.81±21.57比203.87±25.88,PCⅢ(μg/L):69.86±9.32比81.82±7.39,Ⅳ-C(μg/L):204.14±38.97比239.08±24.93,LN(μg/L):162.40±17.39比190.86±15.97,TBil(μmol/L):37.58±27.63比53.06±45.09,DBil(μmol/L):20.55±19.34比30.08±27.39,ALP(U/L):436.50±217.58比469.60±291.69,γ-GGT(U/L):66.78±35.84比87.00±32.82,ALT(U/L):64.75±50.53比75.20±50.19,AST(U/L):77.25±54.23比96.80±59.77,TBA(μmol/L):74.35±44.44比85.45±39.50,LSM(kPa):5.24±0.39比7.53±3.16,APRI:0.52±0.39比0.98±0.29,均P<0.05〕。两组治疗后MDA均较治疗前显著下降,SOD和GSH均较治疗前显著升高;其中利胆合剂组SOD明显高于常规治疗组(kU/L:64.56±6.69比51.58±5.98,P<0.05)。此外,利胆合剂组肝脏回缩时间(d:20.13±10.97比24.33±13.46)和脾脏回缩时间(d:25.93±13.01比29.14±14.52)均较常规治疗组明显缩短(均P<0.05)。结论采用利胆合剂中药治疗胆汁淤积性肝纤维化能有效改善患儿的胆汁淤积、肝纤维化、氧化应激指标及临床症状。

Objective To explore the clinical effect of Li-Dan-He-Ji in the treatment of infantile cholestatic hepatic fibrosis.Methods Patients who met the diagnostic criteria of infantile cholestatic hepatic fibrosis in the department of integrated traditional Chinese and Western medicine and the department of gastroenterology of Wuhan Children's Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from January to December 2021 were included in the study by prospective randomized controlled trial.They were divided into the conventional treatment group and Li-Dan-He-Ji group according to the random number table.The patients in the conventional treatment group were given conventional treatment according to the guidelines.In the Li-Dan-He-Ji group,the self-made Chinese medicinal compound Li-Dan-He-Ji(prescription:Herba Artemisiae Scopariae,Fructus Forsythiae,Radix et Rhizoma Rhei preparata,Radix Polygoni Multiflori Preparata,Radix Paeoniae Rubra,Ramulus Cinnamomi,Fructus Aurantii,Rhizoma Atractylodis Macrocephalae,Fructus Schisandrae Chinensis,Carapax Trionycis,and Radix Glycyrrhizae)was given on the basis of the routine treatment,by oral,enema or nasal feeding,60 mL each day,divided into 2 or 3 times,for 28 days.Outpatient follow-up was maintained for 4 weeks.Before and after treatment,serum liver fibrosis 4 items[typeⅣcollagen(Ⅳ-C),hyaluronidase(HA),typeⅢprocollagen(PCⅢ),laminin(LN)],liver function and cholestasis-related markers[total bilirubin(TBil),direct bilirubin(DBil),total bile acid(TBA),alkaline phosphatase(ALP),γ-glutamyl transpeptidase(γ-GGT),alanine aminotransferase(ALT),aspartate aminotransferase(AST)],oxidative stress markers[superoxide dismutase(SOD),malondialdehyde(MDA),and glutathione(GSH)],liver stiffness measurement(LSM)detected by transient elastography(TE),aspartate aminotransferase-to-platelet ratio index(APRI),and liver and spleen retraction time were recorded in the two groups.Results During the observation period,a total of 40 cases of cholestatic hepatic fibrosis were treated,including 21 cases in the conventional treatment group and 19 cases in the Li-Dan-He-Ji group.Before treatment,the differences in serum liver fibrosis 4 items,serum liver function and cholestasis-related markers,oxidative stress indexes,LSM and APRI of the two groups were not statistically significant.After treatment,the liver fibrosis 4 items,liver function and cholestasis-related markers,LSM,and APRI were all significantly decreased in both groups,and the indexes in the Li-Dan-He-Ji group were significantly lower than those in the conventional treatment group[HA(ng/L):165.81±21.57 vs.203.87±25.88,PCⅢ(μg/L):69.86±9.32 vs.81.82±7.39,Ⅳ-C(μg/L):204.14±38.97 vs.239.08±24.93,LN(μg/L):162.40±17.39 vs.190.86±15.97,TBil(μmol/L):37.58±27.63 vs.53.06±45.09,DBil(μmol/L):20.55±19.34 vs.30.08±27.39,ALP(U/L):436.50±217.58 vs.469.60±291.69,γ-GGT(U/L):66.78±35.84 vs.87.00±32.82,ALT(U/L):64.75±50.53 vs.75.20±50.19,AST(U/L):77.25±54.23 vs.96.80±59.77,TBA(μmol/L):74.35±44.44 vs.85.45±39.50,LSM(kPa):5.24±0.39 vs.7.53±3.16,APRI:0.52±0.39 vs.0.98±0.29,all P<0.05].After treatment,MDA in the two groups were significantly lower than those before treatment,and SOD and GSH were significantly higher than those before treatment.The level of SOD in the Li-Dan-He-Ji group was significantly higher than that in the conventional treatment group(kU/L:64.56±6.69 vs.51.58±5.98,P<0.05).In addition,the liver retraction time(day:20.13±10.97 vs.24.33±13.46)and spleen retraction time(day:25.93±13.01 vs.29.14±14.52)in the Li-Dan-He-Ji group were significantly shorter than those in the conventional treatment group(both P<0.05).Conclusion The use of Li-Dan-He-Ji in the treatment of cholestatic hepatic fibrosis can effectively improve the indicators of cholestasis,hepatic fibrosis,oxidative stress and clinical symptoms in children.