清热化湿疏肝祛瘀法对急性肝内胆汁淤积大鼠的防治作用

目的:观察清热化湿疏肝祛瘀法组成之中药复方对急性肝内胆汁淤积大鼠肝功能的影响。方法:采用异硫氰酸萘酯(ANIT)诱导大鼠急性肝内胆汁淤积,同时以5g/(kg.d)的中药复方进行干预,熊去氧胆酸[90mg/(kg.d)]为对照,于给ANIT后24、48、72h随机处死模型组及各药物干预组1/3数量的大鼠,取肝组织行HE染色在光镜下观察病理学变化,取血清以全自动生化仪检测肝功能。结果:模型组大鼠肝组织损伤及肝功能所测各项指标在应用ANIT后24h、48h及72h均明显增高,并以48h时为高峰;应用中药复方及熊去氧胆酸干预组大鼠的肝功能各项指标在应用ANIT后24h及48h时较相对应的模型组显著下降,72h时则与对应的模型组无统计学差异。结论:清热化湿疏肝祛瘀法中药可明显改善急性肝内胆汁淤积大鼠肝组织损伤及肝功能状况。     

Mechanisms of hepatotoxicity.

This review addresses recent advances in specific mechanisms of hepatotoxicity. Because of its unique metabolism and relationship to the gastrointestinal tract, the liver is an important target of the toxicity of drugs, xenobiotics, and oxidative stress. In cholestatic disease, endogenously generated bile acids produce hepatocellular apoptosis by stimulating Fas translocation from the cytoplasm to the plasma membrane where self-aggregation occurs to trigger apoptosis. Kupffer cell activation and neutrophil infiltration extend toxic injury. Kupffer cells release reactive oxygen species (ROS), cytokines, and chemokines, which induce neutrophil extravasation and activation. The liver expresses many cytochrome P450 isoforms, including ethanol-induced CYP2E1. CYP2E1 generates ROS, activates many toxicologically important substrates, and may be the central pathway by which ethanol causes oxidative stress. In acetaminophen toxicity, nitric oxide (NO) scavenges superoxide to produce peroxynitrite, which then causes protein nitration and tissue injury. In inducible nitric oxide synthase (iNOS) knockout mice, nitration is prevented, but unscavenged superoxide production then causes toxic lipid peroxidation to occur instead. Microvesicular steatosis, nonalcoholic steatohepatitis (NASH), and cytolytic hepatitis involve mitochondrial dysfunction, including impairment of mitochondrial fatty acid beta-oxidation, inhibition of mitochondrial respiration, and damage to mitochondrial DNA. Induction of the mitochondrial permeability transition (MPT) is another mechanism causing mitochondrial failure, which can lead to necrosis from ATP depletion or caspase-dependent apoptosis if ATP depletion does not occur fully. Because of such diverse mechanisms, hepatotoxicity remains a major reason for drug withdrawal from pharmaceutical development and clinical use.     

S-腺苷蛋氨酸联合熊去氧胆酸治疗妊娠期肝内胆汁淤积症的临床疗效及对肝功能、炎症因子的影响

目的 探讨S-腺苷蛋氨酸联合熊去氧胆酸治疗妊娠期肝内胆汁淤积症（ICP）的临床疗效及对肝功能、炎症因子的影响。方法 将100例ICP患者随机分为2组各50例,对照组仅予熊去氧胆酸单药治疗,观察组在对照组的基础上联用S-腺苷蛋氨酸治疗。比较两组治疗前后的瘙痒评分、肝功能指标、血清白介素-12（IL-12）和IL-18水平变化及妊娠结局。结果 治疗后观察组瘙痒评分明显低于对照组,差异有统计学意义（P<0.05）。观察组血清总胆红素（TBIL）、总胆汁酸（TBA）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）水平明显低于对照组,差异有统计学意义（P<0.05）;白细胞介素（IL）-12、IL-18水平明显低于对照组,差异有统计学意义（P<0.05）。观察组早产、羊水污染Ⅱ度、新生儿Apgar评分≤ 7分的发生率明显低于对照组,差异有统计学意义（P<0.05）。结论 S-腺苷蛋氨酸联合熊去氧胆酸治疗ICP疗效优越,可显著改善患者的肝功能及血清炎症因子水平,改善妊娠结局。     

梅毒感染致婴儿胆汁淤积症的诊治进展

近年来,随着成人梅毒感染率的增加,有研究提示在婴儿胆汁淤积症患儿的病因分析中,梅毒感染约占1.45％,梅毒感染作为引起婴儿胆汁淤积症的病因之一,常造成多脏器、多系统的损害.累及肝脏时,多表现为婴儿胆汁淤积症,既可表现为黄疸、皮肤瘙痒、深色尿、陶土便等胆汁淤积症的症状,还可同时合并皮肤黏膜梅毒、骨梅毒、神经系统梅毒等表现.其治疗既包括早期、系统、足量的驱梅治疗,同时还需针对胆汁淤积症进行利胆、退黄、护肝、营养等治疗.该文对梅毒感染所致婴儿胆汁淤积症的病因、临床表现、诊断、治疗以及预防予以综述.     

掌叶大黄蒽醌类衍生物对α-萘异硫氰酸酯所致大鼠黄疸模型的作用

目的观察掌叶大黄蒽醌类衍生物对α-萘异硫氰酸酯(ANIT)所致大鼠急性黄疸模型的退黄降酶作用。方法将W istar大鼠随机分为正常组、模型组、掌叶大黄蒽醌类衍生物高、低剂量组和茵栀黄注射液组。各治疗组连续灌胃给药7 d后,ANIT诱发黄疸模型,48 h后摘眼球取血,分离血清,以血清肝功能指标、SOD的活力及MDA含量以及肝脏组织病理学的改变为观察指标。结果与模型组比较,掌叶大黄蒽醌类衍生物高剂量组和茵栀黄组的ALT、AST、TB IL、ALP、γ-GT、MDA均下降(P<0.01),SOD升高(P<0.01)。肝脏组织病理学检查表明,掌叶大黄蒽醌类衍生物高剂量组能明显减轻肝细胞变性、坏死和肝小胆管增生。与茵栀黄注射液比较,掌叶大黄蒽醌类衍生物高剂量组除TB IL增高(P<0.01)外,其他检测指标差异无显著性(P>0.05)。结论掌叶大黄蒽醌类衍生物具有降低实验性胆汁淤积大鼠血清胆红素、转氨酶和改善肝脏组织损伤的作用。     

TJP2基因突变致进行性家族性肝内胆汁淤积症3例报告及文献复习

目的探讨紧密连接蛋白2(TJP2)基因变异致进行性家族性肝内胆汁淤积症(PFIC)的临床及基因特征。方法总结3例因TJP2基因变异致PFIC患儿的临床资料,并复习相关文献。结果 3例患儿中女性1例、男性2例,均为婴儿期起病;临床以皮肤黄染为主要表现,伴或不伴皮肤瘙痒。血清总胆红素升高,以直接胆红素升高为主,丙氨酸氨基转移酶、天冬氨酸氨基转移酶、总胆汁酸升高,γ-谷氨酰转肽酶(GGT)正常或稍低,提示低GGT胆汁淤积症。二代基因测序发现3例患儿均存在TJP2复合杂合变异,确诊为TJP2变异引起的PFIC 4。文献复习显示,TJP2基因变异可引起PFIC、高胆烷血症、渐进非综合征性耳聋以及近视等儿童疾病。结论采用基因检测技术确诊3例TJP2基因复合杂合变异引起的PFIC 4。     

肝细胞核因子6在小鼠肝内胆管发育过程中的表达

目的 探讨肝细胞核因子6(HNF6)在肝内胆管发育过程中的作用. 方法 用RT-PCR及免疫组织化学等方法 检测HNF6在小鼠胚胎发育的各个阶段以及成年肝中的表达. 结果 RT-PCR结果 显示,HNF6 mRNA的表达在E9d开始出现,与肝芽形成的时间吻合,E13d HNF6 mRNA的表达消失,E15d又重新出现,并一直维持到出生.免疫组织化学显示,CK19免疫反应在E13d开始出现,此时免疫反应阳性细胞在肝索内散在分布.E15d时在近肝门处的门管区丌始出现由单层的、CK19阳性细胞组成的胆管板,之后,阳性细胞反应主要分布于胆管板和小叶间胆管.E9～11d,多数肝索细胞呈HNF6阳性反应,E13d的肝索中未观察剑HNF6的表达.E15～17d,HNF6阳性反应的分布与CK19相似,成年小鼠肝的胆管上皮细胞仍呈HNF6阳性反应. 结论 HNF6可能与肝干细胞的特化关系不大,而与肝发育的启动、肝干细胞向胆管上皮细胞的分化及其分化状态的维持有关.     

Plasma exchange treats severe intrahepatic cholestasis caused by dacomitinib: A case report

Rationale:Dacomitinib-induced liver injury is often manifested by mild elevations of transaminases and bilirubin, and severe intrahepatic cholestasis caused by dacomitinib for simultaneous taking orally cytochrome P450 2D6 (CYP2D6) competitive substrates has been rarely reported.Patient concerns:The patient was a 69-year-old woman with non–small cell lung cancer (NSCLC) who was prescribed oral dacomitinib for a month; she was given oral loratadine due to “allergic rhinitis” and metoprolol extended action tablets due to “tachycardia” separately for a few days during the course of dacomitinib treatment. The patient developed liver damage, increased fatigue, yellow urine, and pruritus, with significantly elevated serum levels of bilirubin and glutamyltranspetidase.Diagnosis:Intrahepatic cholestasis, drug-induced liver injury, and NSCLC.Interventions:After admission, the patient was prescribed adenosylmethionine, acetylcysteine, ursodeoxycholic acid capsule, methylprednisolone and fenofibrate for a month, with progressive elevation of liver biochemical parameters. Through drug enzyme gene assays in the liver tissue after percutaneous liver biopsy, we found both CYP2D6*10/*10 and ATP-binding cassette subfamily B member 1 GG variants (rs1045642) positive. After the poor response to the conventional medication, the patient underwent plasma exchange.Outcomes:The patient was discharged after her liver parameters improved; the parameters remained normal at several follow-up visits, and she renewed the NSCLC regimens without dacomitinib after being evaluated by oncologists.Lessons:Dacomitinib can induce severe intrahepatic cholestasis. It is considered that patients with intermediate metabolic CYP2D6 are susceptible to drug-induced liver injury caused by dacomitinib; plasma exchange may be an effective treatment.     

中西医结合治疗妊娠肝内胆汁淤积症的临床疗效评价

目的研究中西医结合治疗（IC P ）妊娠肝内胆汁淤积症的临床疗效。方法2008年2月至2012年2月在恩施州中心医院妇产科IC P患者184例,分为中医组（90例）和中西医结合组（94例）,对临床资料进行回顾和分析。结果中医组90例中,早产儿16例（17．78％）,胎儿宫内窘迫12例（13．33％）,剖宫产59例（65．56％）,1例围产儿死亡（1．11％）,产后出血3例（3．33％）。中西医结合组94例中,17例早产（18．09％）,胎儿宫内窘迫14例（14．89％）,剖宫产60例（63．83％）,产后出血2例（2．13％）。两组患者妊娠结果差异均有统计学意义。结论早期诊断、综合治疗、密切监测、及时终止妊娠是降低IC P患者围生儿死亡和产后出血的主要措施。     

妊娠期肝内胆汁淤积症脐血淋巴细胞凋亡的初步研究

目的 探讨脐血淋巴细胞凋亡在妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)发病中的意义.方法 采用流式细胞技术分析ICP患者和正常妊娠妇女脐血淋巴细胞的凋亡率;通过免疫细胞化学染色技术检测ICP患者和正常妊娠妇女脐血淋巴细胞上凋亡调控基因Fas、FasL、Bcl-2的蛋白表达.结果 ICP患者脐血淋巴细胞凋亡率低于正常妊娠组(P＜0.001),脐血淋巴细胞上Fas、Bcl-2表达水平两组间差异无统计学意义(P＞0.05),而FasL表达水平在ICP组高于正常妊娠组(P＜0.005).结论 ICP患者存在脐血淋巴细胞凋亡率及凋亡调控基因表达的异常,可能致移植物抗宿主反应异常而在ICP的发病中起一定作用.