丁二磺酸腺苷蛋氨酸联合熊去氧胆酸对妊娠期肝内胆汁淤积症患者胆汁酸、肝功能及妊娠结局的影响

Effects of S-adenosyl-L-methionine combined with ursodeoxycholic acid on bile acid, liver function and pregnancy outcomes of patients with intrahepatic cholestasis of pregnancy

目的探讨丁二磺酸腺苷蛋氨酸(S-adenosyl-L-methionine,SAMe)联合熊去氧胆酸(ursodesoxycholic acid,UDCA)对妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)患者胆汁酸、肝功能及妊娠结局的影响。方法选取2014年10月至2018年10月于湖北医药学院附属东风医院就诊的102例ICP患者为研究对象。采用随机、对照平行分组分为UDCA组(51例)和UDCA联合SAMe组(51例),两组患者均进行常规对症治疗,UDCA组给予UDCA,UDCA联合SAMe组在UDCA治疗基础上给予SAMe,记录两组患者治疗前、治疗第3 d和第5 d的瘙痒评分,治疗前及治疗14 d的胆汁酸、肝功能[肝胆酸(courage acid,CG)、丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartate aminotransferase,AST)]和免疫功能[白细胞介素-17(interleukin 17,IL-17)、转化生长因子-β(transforming growth factor-β,TGF-β)及细胞因子信号转导负调控因子(suppressors of cytokine signaling,SOCS)],评估两组妊娠结局和不良反应。结果治疗前、治疗第3 d和治疗第5 d,UDCA联合SAMe组患者瘙痒评分分别为(15.38±3.89)分、(4.42±1.05)分和(1.22±0.68)分,UDCA组分别为(15.31±3.76)分、(8.02±2.28)分和(3.08±1.08)分,均显著低于治疗前(P均<0.05),治疗第3 d和治疗第5 d,UDCA联合SAMe组患者瘙痒评分均显著低于UDCA组,差异有统计学意义(t=10.242、10.408,P均<0.001)。UDCA联合SAMe组患者瘙痒症状缓解时间为(3.50±1.08)d,显著低于UDCA组的(5.74±1.27)d(t=9.595,P <0.001)。治疗14 d后,UDCA联合SAMe组患者总胆汁酸(total bile acid,TBA)、CG、ALT、AST和TBil分别为(13.24±2.15)μmol/L、(16.10±3.56)mg/L、(45.35±9.38)U/L、(52.21±9.31)U/L和(15.21±3.25)μmol/L,UDCA组分别为(19.53±4.49)μmol/L、(21.02±5.02)mg/L、(70.36±13.54)U/L、(72.64±15.84)U/L和(18.51±4.07)μmol/L,均显著低于各组治疗前(P均<0.05),且UDCA联合SAMe组上述各指标水平均显著低于UDCA组(P均<0.05)。治疗14 d后,UDCA联合SAMe组和UDCA组患者IL-17分别为(2.25±0.56)ng/L、(3.49±0.67)ng/L,均显著低于治疗前的(5.82±1.21)ng/L和(5.85±1.25)ng/L,差异有统计学意义(t=28.808、17.556,P均<0.001),且UDCA联合SAMe组显著低于UDCA组(t=10.141,P均<0.001)。治疗14 d后,UDCA联合SAMe组TGF-β和SOCS蛋白水平分别为(5.82±1.24)ng/L和(408.23±55.56)ng/L,UDCA组分别为(3.89±0.76)ng/L和(328.13±42.72)ng/L,两组间差异均有统计学意义(t=9.477、10.286,P <0.001)。UDCA联合SAMe组剖宫产、早产及胎儿宫内窘迫发生率分别为15.69%(8/51)、9.80%(5/51)和3.92%(2/51),均显著低于UDCA组的33.33%(17/51)、29.41%(15/51)和17.65%(9/51),差异有统计学意义(χ2=4.292、6.220、4.993,P=0.038、0.013、0.025)。UDCA联合SAMe组新生儿Apgar评分为(8.68±0.99)分,高于UDCA组的(7.36±1.56)分,差异均有统计学意义(t=5.102,P <0.001)。两组患者均未出现药物不良反应。结论 SAMe联合UDCA治疗ICP患者的疗效确切,可缓解瘙痒,有效减少肝内胆汁酸淤积,改善肝功能,纠正免疫功能紊乱,利于母婴良好结局发展,用药安全性高。

Objective To investigate the effects of S-adenosyl-L-methionine(SAMe) combined with ursodeoxycholic acid(UDCA) on bile acid, liver function and pregnancy outcomes of patients with intrahepatic cholestasis of pregnancy(ICP). Methods Total of 102 patients with ICP in Dongfeng Hospital Affiliated to Hubei University of Medicine from October 2014 to October 2018 were enrolled. The patients were divided into UDCA group(51 cases) and UDCA combined with SAMe group(51 cases) by randomized and controlled parallel grouping. All patients were given conventional symptomatic treatment. Patients in UDCA group were given UDCA, while patients in UDCA combined with SAMe group were given SAMe based on UDCA treatment. The pruritus before treatment and on the third day and the fifth day of treatment, bile acid, liver function [cholyglycine(CG), alanine aminotransferase(ALT), aspartate aminotransferase(AST)] and immune function [interleukin 17(IL-17), transforming growth factor-β(TGF-β), suppressors of cytokine signaling(SOCS)] before and 14 d after treatment were observed in both groups. The pregnancy outcomes and adverse reactions were also evaluated. Results Before treatment, on the third day and the fifth day of treatment, the pruritus scores were(15.38 ± 3.89) points,(4.42 ± 1.05) points and(1.22 ± 0.68) points in UDCA combined with SAMe group respectively, and(15.31 ± 3.76) points,(8.02 ± 2.28) points and(3.08 ± 1.08) points in UDCA group, respectively, which were significantly lower than those before treatment(all P < 0.05). On the third day and fifth day of treatment, the pruritus scores of patients in UDCA combined with SAMe group were significantly lower than those in UDCA group(t = 10.242, 10.408, all P < 0.001). The remission time of pruritus in UDCA combined with SAMe group was significantly shorter than that in UDCA group [(3.50 ± 1.08) d vs(5.74 ± 1.27) d, t = 9.595, P < 0.001). After 14 d of treatment, levels of TBA, CG, ALT, AST and TBil were(13.24 ± 2.15) μmol/L,(16.10 ± 3.56) mg/L,(45.35 ± 9.38) U/L,(52.21 ± 9.31) U/L and(15.21 ± 3.25) μmol/L in UDCA combined with SAMe group respectively, and(19.53 ± 4.49) μmol/L,(21.02 ± 5.02) mg/L,(70.36 ± 13.54) U/L,(72.64 ± 15.84) U/L and(18.51 ± 4.07) μmol/L in UDCA group, respectively, which were significantly lower than those before treatment(all P < 0.05), and the above indexes of patients in UDCA combined with SAMe group were significantly lower than those in UDCA group(all P < 0.05). After treatment for 14 d, the serum interleukin-17(IL-17) level of patients in UDCA combined with SAMe group and UDCA group were(2.25 ± 0.56) ng/L and(3.49 ± 0.67) ng/L, respectively, which were significantly lower than those before treatment [(5.82 ± 1.21)ng/L,(5.85 ± 1.25) ng/L], the differences were statistically significant(t = 28.808, 17.556;P < 0.001). The IL-17 levels of patients in UDCA combined with SAMe group was significantly lower than that in UDCA group(t = 10.141, P < 0.001). After treatment for 14 d, the TGF-β and SOCS of patients in UDCA combined with SAMe group were(5.82 ± 1.24) ng/L and(408.23 ± 55.56) ng/L, respectively, which were(3.89 ± 0.76) ng/L and(328.13 ± 42.72) ng/L in UDCA group, respectively, the differences were statistically significant(t = 9.477, 10.286;P < 0.001). The incidence rates of cesarean section, premature delivery and intrauterine fetal distress in UDCA combined with SAMe group were 15.69%(8/51), 9.80%(5/51) and 3.92%(2/51), respectively, which were significantly lower than those in UDCA group [33.33%(17/51), 29.41%(15/51) and 17.65%(9/51)], the differences were statistically significant(χ2 = 4.292, 6.220, 4.993;P = 0.038, 0.013, 0.025). The neonatal Apgar score in UDCA combined with SAMe group was significantly higher than that in UDCA group [(8.68 ± 0.99) points vs(7.36 ± 1.56) points], the difference was statistically significant(t = 5.102, P < 0.001). There were no adverse drug reactions in both groups. Conclusions The efficacy of SAMe combined with UDCA in treatment of ICP was exact, which can promote the recovery of pruritus symptoms, effectively reduce intrahepatic bile acid deposition, improve liver function, correct immune dysfunction, and facilitate the good outcomes of maternal-infant, and with high clinical safety.