Clinical effect of ursodeoxycholic acid combined with diammonium glycyrrhizinate in treatment of primary biliary cholangitis
-
摘要:
目的对比熊去氧胆酸(UDCA)联合甘草酸二铵与单用UDCA治疗原发性胆汁性胆管炎(PBC)的生化学应答和肝脏硬度变化情况。方法选取2014年1月-2016年3月就诊于河北医科大学第三医院中西医结合肝病科的PBC患者66例,均行FibroTouch检测,以肝脏硬度值表示肝纤维化程度,对比分析UDCA联合甘草酸二铵与单用UDCA治疗PBC患者4、12、24和48周的肝生化学应答和治疗24、48周后肝脏硬度值变化情况。两组间计量资料比较采用两独立样本t检验,治疗前后生化学指标及肝脏硬度值比较采用配对t检验。结果 UDCA联合甘草酸二铵治疗组与单用UDCA对照组比较,联合治疗组AST水平在治疗后4周[(38. 4±15. 4) U/L vs (61. 6±28. 8) U/L,t=2. 684,P=0. 012]、12周[(36. 4±12. 6) U/L vs (58. 1±24. 8) U/L,t=2. 953,P=0. 006)]、24周[(37. 0±8. 5) U/L vs (52. 9±17. 2) U/L,t=3. 134,P=0. 004]、48周[(34. 9±7. 9) U...
Abstract:Objective To investigate the clinical effect of ursodeoxycholic acid (UDCA) alone or in combination with diammonium glycyrrhizinate on biochemical response and liver stiffness measurement (LSM) in the treatment of primary biliary cholangitis (PBC) . Methods A total of 66 patients with PBC who visited Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, from January 2014 to March 2016 were enrolled. The FibroTouch test was performed, and LSM was used to indicate the degree of liver fibrosis. The patients treated with UDCA and diammonium glycyrrhizinate (treatment group) and those treated with UDCA alone (control group) were compared in terms of liver biochemical response at 4, 12, 24, and 48 weeks of treatment and LSM at 24 and 48 weeks of treatment. The independent samples t-test was used for comparison of continuous data between two groups, and the paired t-test was used for comparison of biochemical parameters and LSM before and after treatment. Results Compared with the control group, the treatment group had a significantly lower level of aspartate aminotransferase at 4, 12, 24, and 48 weeks of treatment (4 weeks: 38. 4 ± 15. 4 U/L vs61. 6 ± 28. 8 U/L, t = 2. 684, P = 0. 012; 12 weeks: 36. 4 ± 12. 6 U/L vs 58. 1 ± 24. 8 U/L, t = 2. 953, P = 0. 006; 24 weeks: 37. 0 ± 8. 5 U/L vs 52. 9 ± 17. 2 U/L, t = 3. 134, P = 0. 004; 48 weeks: 34. 9 ± 7. 9 U/L vs 48. 6 ± 12. 7 U/L, t = 3. 463, P = 0. 002) , as well as a significantly lower level of alkaline phosphatase at 24 and 48 weeks of treatment (24 weeks: 91. 6 ± 15. 1 U/L vs 137. 3 ± 55. 6 U/L, t =2. 970, P = 0. 006; 48 weeks: 71. 3 ± 14. 7 U/L vs 128. 7 ± 45. 5 U/L, t = 4. 503, P < 0. 001) . There was a significant reduction in LSM at 24 and 48 weeks of treatment in the control group (24 weeks: 12. 9 ± 6. 8 kPa vs 13. 9 ± 7. 6 k Pa, t = 4. 814, P < 0. 001; 48 weeks:12. 6 ± 6. 4 kPa vs 13. 9 ± 7. 6 kPa, t = 3. 928, P = 0. 010) and the treatment group (24 weeks: 13. 4 ± 7. 0 kPa vs 15. 8 ± 9. 7 k Pa, t =3. 031, P = 0. 010; 48 weeks: 12. 0 ± 5. 7 kPa vs 15. 8 ± 9. 7 kPa, t = 3. 044, P = 0. 010) ; however, there was no significant difference in LSM between the control group and the treatment group at 24 and 48 weeks of treatment (all P > 0. 05) . Conclusion In patients with PBC, UDCA combined with diammonium glycyrrhizinate can improve serum biochemical response and has a better clinical effect than UDCA alone.Both groups have a significant reduction in LSM at 24 and 48 weeks of treatment, suggesting that UDCA combined with diammonium glycyrrhizinate can help to maintain disease stability.
-
急性胰腺炎(acute pamcreatitis,AP)是临床常见消化系统急腹症之一[1],近年来,其发病率不断上升[2]。Yokoe等[3]研究显示,15%~20%的AP进展为重症急性胰腺炎(severe acute pancreatic, SAP)。脓毒症是病原微生物侵入血液引起的全身感染性疾病,据Sagana等[4]报道美国每年约有0.6%的人发生脓毒症。SAP病情凶险极易引发脓毒症,SAP一旦发生脓毒症不仅加重医疗费用负担、延长住院时间,还可能并发脓毒性休克,多器官功能障碍,病情进展甚至会引起死亡[5],临床诊治极为困难。本研究回顾性分析SAP患者的临床资料,分析SAP患者并发脓毒症的相关因素,旨在为临床防治提供参考。
1. 资料与方法
1.1 研究对象
收集2007年1月—2020年3月贵州医科大学第三附属医院与黔南州人民医院收治的SAP患者临床资料。SAP诊断标准参考中华医学会制定的《急性胰腺炎诊治指南(2014)》[6]。脓毒症诊断标准参照国家卫生健康委颁发的《医院感染诊断标准(试行)》[7]。纳入标准:(1)年龄≥16周岁;(2)符合SAP诊断。剔除标准:(1)病历记录不全;(2)伴有恶性肿瘤晚期或使用糖皮质激素患者;(3)入院手术前已合并脓毒症者;(4)伴有其他部位原发性感染者。
1.2 研究方法
根据SAP是否发生脓毒症分为脓毒症与非脓毒症,记录每例患者年龄、性别、APACHEⅡ评分、血糖、血钙、血清总胆固醇、血清甘油三酯、血尿素氮、血清白蛋白、血清肌酐、胰腺坏死范围所占比例,以及入住ICU、低氧血症、深静脉置管、机械通气、预防性使用抗生素、血液净化、手术病灶坏死组织清除方式、留置导尿情况,血培养检出病原菌种类等临床资料。本研究所纳入SAP患者采取急诊手术清除病灶坏死组织,手术方式分为开腹与腹腔镜两种方式。
1.3 伦理学审查
本研究通过贵州医科大学第三附属医院伦理委员会审批,批号:2020-002,并经患者及家属知情同意。
1.4 统计学方法
采用SPSS 24.0软件进行数据分析。计量资料以x±s表示,两组间比较采用t检验,计数资料两组间比较采用χ2检验。多因素分析采用logistic回归分析。P < 0.05为差异有统计学意义。
2. 结果
2.1 一般资料
研究共纳入SAP患者178例,其中男106例、女72例, 年龄16~77岁,平均(49.69±14.77) 岁。发生脓毒症56例(31.46%),其中男36例、女20例,平均(51.29±13.92)岁。
2.2 脓毒症菌种分布
在56例SAP并发脓毒症患者血培养中共分离出61株病原菌,其中革兰阳性菌14株,占22.95%,革兰阴性菌39株,占63.93%,真菌8株,占13.11%(表 1)。
表 1 SAP合并脓毒症患者的菌种构成比病原菌 株数(n=61) 构成比(%) 革兰阳性菌 14 22.95 表皮葡萄球菌 8 13.11 溶血葡萄球菌 4 6.56 粪肠球菌 2 3.28 革兰阴性菌 39 63.93 肺炎克雷伯菌 11 18.03 鲍曼不动杆菌 9 14.75 铜绿假单胞菌 9 14.75 大肠埃希菌 7 11.48 嗜麦芽窄食假单胞菌 2 3.28 阴沟肠杆菌 1 1.64 真菌 8 13.11 白色假丝酵母菌 5 8.20 光滑假丝酵母菌 2 3.28 热带假丝酵母菌 1 1.64 2.2 单因素分析
单因素分析显示,APACHEⅡ评分、血糖、血钙、血清总胆固醇、血清甘油三酯、血尿素氮、血清肌酐、血清白蛋白,以及入住ICU、低氧血症、深静脉置管、机械通气、手术方式、血液净化、留置导尿、胰腺坏死范围在脓毒症和非脓毒症患者间差异均有统计学意义(P值均 < 0.05)(表 2)。
表 2 SAP并发脓毒症的单因素分析因素 非脓毒症(n=122) 脓毒症(n=56) 统计值 P值 年龄(岁) 48.95±15.14 51.29±13.92 t=1.011 0.314 男/女(例) 70/52 36/20 χ2=0.761 0.383 APACHEⅡ评分(分) 24.35±5.86 27.71±5.56 t=3.683 < 0.001 入住ICU(例) 41 31 χ2=7.538 0.006 低氧血症(例) 36 31 χ2=10.926 0.001 深静脉置管(例) 82 46 χ2=4.235 0.040 机械通气(例) 44 30 χ2=4.842 0.028 血糖(mmol/L) 11.37±3.80 13.13±4.34 t=2.596 0.011 预防性使用抗生素(例) 51 21 χ2=0.295 0.587 手术方式(例) χ2=8.249 0.004 腹腔镜 43 8 开腹 79 48 血液净化(例) 83 29 χ2=4.343 0.037 留置导尿(例) 34 34 χ2=17.539 < 0.001 胰腺坏死范围(例) χ2=13.386 0.001 >50% 9 12 30%~50% 39 25 < 30% 74 19 血钙(mmol/L) 2.26±0.32 2.14±0.33 t=-2.144 0.034 血清总胆固醇(mmol/L) 6.13±2.26 7.03±2.20 t=2.498 0.014 血清甘油三酯(mmol/L) 2.02±1.12 2.59±1.23 t=2.946 0.004 血尿素氮(mmol/L) 7.13±2.52 9.05±4.56 t=2.951 0.004 血清肌酐(μmol/L) 116.46±46.78 147.87±67.31 t=3.160 0.002 血清白蛋白(g/L) 36.08±7.95 32.62±10.22 t=-2.246 0.027 2.3 多因素分析
将单因素分析中有统计学意义的指标纳入logistic多因素回归分析,结果显示,APACHEⅡ评分、低氧血症、血糖、胰腺坏死范围、血清肌酐是SAP并发脓毒症的独立危险因素,采用腹腔镜清除病灶坏死组织为SAP并发脓毒症的独立保护因素(P值均 < 0.05)(表 3)。
表 3 SAP并发脓毒症的多因素分析变量 B SE Wald P值 OR 95%CI APACHEⅡ评分(分) 1.909 0.574 11.063 0.001 6.748 2.191~20.788 入住ICU 0.994 0.652 2.321 0.128 2.701 0.752~9.700 低氧血症 1.219 0.568 4.607 0.032 3.383 1.112~10.293 深静脉置管 0.577 0.677 0.728 0.394 1.781 0.473~6.710 机械通气 0.750 0.560 1.794 0.180 2.118 0.706~6.350 血糖(mmol/L) 1.665 0.767 4.714 0.030 5.288 1.176~23.781 手术方式(腹腔镜) -1.387 0.682 4.133 0.042 0.250 0.066~0.951 血液净化 -0.185 0.554 0.112 0.738 0.831 0.280~2.463 留置导尿 0.636 0.559 1.293 0.256 1.889 0.631~5.651 胰腺坏死范围 1.709 0.640 7.130 0.008 5.523 1.575~19.360 血钙(mmol/L) -0.964 0.586 2.710 0.100 0.381 0.121~1.202 血清总胆固醇(mmol/L) 0.498 0.593 0.703 0.402 1.645 0.514~5.263 血清甘油三酯(mmol/L) 0.740 0.840 0.777 0.378 2.097 0.404~10.880 血尿素氮(mmol/L) 1.066 0.630 2.862 0.091 2.903 0.845~9.977 血清肌酐(μmol/L) 1.612 0.671 5.771 0.016 5.012 1.345~18.672 血清白蛋白(g/L) -0.719 0.705 1.041 0.308 0.487 0.122~1.939 3. 讨论
SAP是常见消化系统急症,后期继发感染性胰腺坏死的概率较高[8-9]。脓毒症是SAP的严重并发症之一,也是患者后期死亡的重要原因。本研究显示,在178例SAP患者中发生脓毒症56例(31.46%),与陈莎燕等[10]报道结果相近,提示SAP患者并发脓毒症的概率较高,直接影响治疗的预后,临床应予以注意。本研究在56例SAP并发脓毒症患者血培养中共分离出61株病原菌,其中革兰阳性球菌14株,占22.95%,革兰阴性杆菌39株,占63.93%,真菌8株,占13.11%,与廖全凤等[11]研究结果相似,临床应根据其感染病原菌特点选用抗菌药物。
APACHE-Ⅱ评分是判断SAP严重程度与预后的重要评分系统,评分越高提示病情越严重,免疫功能越差,病原菌越易进入血液形成脓毒症[12];SAP胰腺组织灌注不足,此时合并低氧血症可增加胰腺组织缺氧程度与坏死范围,导致胰腺感染增加并侵入血流[13],同时SAP常伴发肺部感染等胰腺外感染,后者又可加重SAP患者的感染严重程度,严重者引起低氧血症与呼吸功能衰竭,甚至发生多器官功能衰竭风险[14];胰腺的内分泌部分泌的胰岛素是调节血糖的重要激素,SAP胰腺坏死损伤胰岛导致胰岛素分泌不足,糖代谢紊乱,血糖升高,有利于病原菌入侵,同时其免疫功能下降,更利于病原菌入侵血流,增加脓毒症的发生[15]。肌酐是肌肉代谢产物, 肌肉中肌酸通过非酶脱水反应产生,再释放进入血液中,随尿排出体外。因此血清肌酐与人体肌肉总量密切相关,而不易受饮食等影响;再加上肌酐为小分子物质,通过肾小球滤过,很少被肾小管吸收,每日体内产生量几乎均随尿排出,不受尿量影响,因此,临床上将血清肌酐作为肾功能重要指标之一,血清肌酐升高提示肾功能受损[16];本研究显示,血清肌酐与脓毒症密切相关,可能原因为肾功能不全时白细胞趋化性功能受损,淋巴细胞功能障碍,体内免疫球蛋白降低,免疫功能下降,容易发生脓毒症[17-18]。手术病灶清除引流是治疗感染性胰腺坏死的重要手段[19];感染性胰腺坏死病灶清除引流手术的方式有开腹与微创手术两种,手术可清除炎性病灶减少感染,但是开放手术创伤大,可引起坏死炎性胰腺组织扩散,感染病原菌侵入血流,同时开腹手术破坏人体自然屏障,外界环境中的病原菌也易通过切口侵入引起脓毒症[20],而微创手术方式既可清除炎性坏死组织,又可减少外界病原菌侵入,可减少脓毒症[21]。胰腺坏死程度越高提示感染性胰腺坏死病灶越大,产生的炎性坏死组织越多,对周围组织破坏也越大,病原菌越易侵入血流产生胰外感染[22]。多因素分析显示,APACHEⅡ评分、低氧血症、血糖、胰腺坏死程度高、血清肌酐等因素是SAP并发脓毒症的独立危险因素,采用微创手术方式清除病灶坏死组织为SAP并发脓毒症的独立保护因素。
总之,SAP并发脓毒症与多因素相关。控制血糖,保护肺肾等重器官功能,采用微创手术方式清除病灶坏死组织,注意重症、胰腺坏死程度高患者的救治是减少SAP并发脓毒症的重要措施。
-
[1]LINDOR KD, BOWLUS CL, BOYER J, et al.Primary biliary cholangitis:2018 practice guidance from the American Association for the Study of Liver Diseases[J].Hepatology, 2019, 69 (1) :394-419. [2]European Association for the Study of the Liver.EASL Clinical Practice Guidelines:The diagnosis and management of patients with primary biliary cholangitis[J].J Hepatol, 2017, 67 (1) :145-172. [3]Chinese Society of Hepatology, Chinese Medical Association;Chinese Society of Gastroenterology, Chinese Medical Association;Chinese Society of Infectious Diseases, Chinese Medical Association.Consensus on the diagnosis and management of primary biliary cirrhosis (cholangitis) (2015) [J].J Clin Hepatol, 2015, 31 (12) :1980-1988. (in Chinese) 中华医学会肝病学分会, 中华医学会消化病学分会, 中华医学会感染病学分会.原发性胆汁性肝硬化 (又名原发性胆汁性胆管炎) 诊断和治疗共识 (2015) [J].临床肝胆病杂志, 2015, 31 (12) :1980-1988. [4] Chinese Expert Committee for the diagnosis and treatment of cholestasis liver disease.Chinese expert consensus guidelines for the diagnosis and treatment of cholestasis liver disease reached in 2013[J/CD].Chin J Exp Clin Infect Dis:Electronic Edition, 2013, 7 (1) :134-144. (in Chinese) 胆汁淤积性肝病诊断治疗专家委员会.胆汁淤积性肝病诊断治疗专家共识2013[J/CD].中华实验和临床感染病杂志:电子版, 2013, 7 (1) :134-144. [5]ZHANG LN, SHI TY, SHI XH, et al.Early biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis:Results of a 14-year cohort study[J].Hepatology, 2013, 58 (1) :264-272. [6]CZUL F, LEVY C.Novel therapies on primary biliary cirrhosis[J].Clin Liver Dis, 2016, 20 (1) :113-130. [7]CORPECHOT C, ABENAVOLI L, RABAHI N, et al.Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis[J].Hepatology, 2008, 48 (3) :871-877. [8]NEVENS F, ANDREONE P, MAZZELLA G, et al.A placebocontrolled trial of obeticholic acid in primary biliary cholangitis[J].N Engl J Med, 2016, 375 (7) :631-643. [9]KOWDLEY KV, LUKETIC V, CHAPMAN R.A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis[J].Hepatology, 2018, 67 (5) :1890-1902. [10]DUAN WJ, OU XJ, WANG XM, et al.Efficacy and safety of fenofibrate add-on therapy for patients with primary biliary cholangitis and a suboptimal response to UDCA[J].Rev Esp Enferm Dig, 2018, 110 (9) :557-563. [11]ZHANG L, FAN YJ, TAN B, et al.Recognition of the clinical application and biological mechanism of ursodeoxycholic acid in liver diseases[J].Chin J Clin Pharmacol Ther, 2017, 22 (2) :233-240. (in Chinese) 张林, 樊玉娟, 谭波, 等.熊脱氧胆酸在慢性肝病中应用及机制的再认识[J].中国临床药理学与治疗学, 2017, 22 (2) :233-240. [12] CHEN JL, YANG X, ZHANG Q, et al.Effect of ursodeoxycholic acid with traditional Chinese medicine on biochemical response in patients with primary biliary cholangitis:A realworld cohort study[J].Chin J Hepatol, 2018, 26 (12) :909-915. (in Chinese) 陈佳良, 杨雪, 张群, 等.熊去氧胆酸联合中药治疗对原发性胆汁性胆管炎患者生物化学应答的影响:一项基于真实世界的队列研究[J].中华肝脏病杂志, 2018, 26 (12) :909-915. [13]ZHAO ZB, LIAN ZX.Immunological pathogenesis of primary biliary cholangitis[J].J Clin Hepatol, 2017, 33 (11) :2112-2116. (in Chinese) 赵志斌, 廉哲雄.原发性胆汁性胆管炎的免疫学发病机制[J].临床肝胆病杂志, 2017, 33 (11) :2112-2116. [14]CORPECHOT C, CARRAT F, POUJOL-ROBERT A, et al.Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis[J].Hepatology, 2012, 56 (1) :198-208. [15]CARBONE M, SHARP SJ, FLACK S, et al.The UK-PBC risk scores:Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis[J].Hepatology, 2016, 63 (3) :930-950. [16]LAMMERS WJ, HIRSCHFIELD GM, CORPECHOT C, et al.Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy[J].Gastroenterology, 2015, 149 (7) :1804-1812. 期刊类型引用(0)
其他类型引用(1)
-