肝移植术后肝脏淋巴回流淤滞发生的影响因素初步临床分析

目的:分析肝移植术后肝脏淋巴回流淤滞(Intrahepatic lymphatic stasis,IHLS)的影响因素。方法:收集我院自2004~2012年期间行肝移植手术并经增强计算机断层扫描(Computed tomography,CT)和/或磁共振(Magnetic resonance imaging,MRI)确诊的IHLS病人,分析正常肝移植组IHLS阳性率与肝移植术后静脉并发症、胆道并发症、乙肝复发、肝癌复发、动脉并发症、移植排斥、药物性肝损害、转移瘤组IHLS阳性率的差异。结果:正常移植肝组术后IHLS的阳性率分别与术后胆道并发症、静脉并发症、乙肝复发组肝移植术后IHLS的阳性率差异有统计学意义(P0.05),与其他并发症组IHLS的阳性率差异无统计学意义(P0.05)。结论:肝移植术后静脉并发症、胆道并发症及乙肝复发可影响肝移植术后IHLS发生。     

Short- and medium-chain fatty acids enhance the cell surface expression and transport capacity of the bile salt export pump (BSEP/ABCB11)

The reduced expression of the bile salt export pump (BSEP/ABCB11) at the canalicular membrane is associated with cholestasis-induced hepatotoxicity due to the accumulation of bile acids in hepatocytes. We previously reported that 4-phenylbutyrate (4PBA), an approved drug for urea cycle disorders, is a promising agent for intrahepatic cholestasis because it increases both the cell surface expression and the transport capacity of BSEP. In the present study, we searched for effective compounds other than 4PBA by focusing on short- and medium-chain fatty acids, which have similar characteristics to 4PBA such as their low-molecular-weight and a carboxyl group. In transcellular transport studies using Madin–Darby canine kidney (MDCK) II cells, all short- and medium-chain fatty acids tested except for formate, acetate, and hexanoic acid showed more potent effects on wild type (WT) BSEP-mediated [³H]taurocholate transport than did 4PBA. The increase in WT BSEP transport with butyrate and octanoic acid treatment correlated with an increase in its expression at the cell surface. Two PFIC2-type variants, E297G and D482G BSEP, were similarly affected with both compounds treatment. The prolonged half-life of cell surface-resident WT BSEP was responsible for this increased octanoic acid-stimulated transport, but not for that of butyrate. In conclusion, short- and medium-chain fatty acids have potent effects on the increase in WT and PFIC2-type BSEP-mediated transport in MDCK II cells. Although both short- and medium-chain fatty acids enhance the transport capacity of WT and PFIC2-type BSEP by inducing those expressions at the cell surface, the underlying mechanism seems to differ between fatty acids.     

妊娠肝内胆汁淤积症胎儿猝死发病机制的研究进展

妊娠肝内胆汁淤积症（ICP）妊娠晚期胎儿猝死,难以预料和准确监测,具有高风险性。目前其机制不明。孕妇和胎儿高胆汁酸水平对胎盘功能的影响和对胎儿的损伤是当前研究的主要方向。特别是一系列胆汁酸对心肌细胞毒性作用的实验,提示胆汁酸对胎儿心脏的毒性作用可能是引起胎儿猝死的重要原因。     

超声引导下肝内胆管置管治疗肝内胆管结石并发梗阻的临床效果观察

目的:探究超声引导下肝内胆管置管治疗肝内胆管结石并发梗阻的临床效果和安全性。方法:选择2014年1月至2018年1月于我院接受治疗的98例肝内胆管结石并发梗阻患者为研究对象,将患者按照入院顺序统一编号后,根据随机数字表法进行分为实验组与对照组,每组各49例患者。对照组患者于常规X线引导下行肝内胆管置管治疗,实验组患者在超声引导下实施肝内胆管置管治疗,对比两组患者穿刺次数、手术时间、术后并发症的发生情况,并对两组患者随访3个月,比较其结石残余率及治疗效果。结果:(1)实验组患者穿刺次数及操作时间均显著少于对照组(P0.05);(2)实验组患者术后各类并发症发生率为4.08%,明显低于对照组(20.41%,P0.05);(3)对照组患者后3个月的结石残余率为14.29%(7/49),实验组为2.04%(1/49),显著低于对照组(P0.05);(4)术后3个月,实验组患者治疗总有效率为97.96%,明显高于对照组(81.63%,P0.05)。结论:与常规X线引导下行肝内胆管置管治疗相比,超声引导下肝内胆管置管在治疗肝内胆管结石并发梗阻中具有较更好的治疗效果和安全性。     

Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1

Functional defects in ATPase class I type 8B membrane 1 (ATP8B1 or familial intrahepatic cholestasis 1, FIC1) lead to cholestasis by mechanism(s) that are not fully understood. One proposed pathophysiology involves aberrant signaling to the bile acid sensor, the farnesoid X receptor (FXR), via protein kinase C ζ (PKCζ). The following cell line-based studies investigated whether phospholipase D2 may transduce a signal from FIC1 to FXR. PLD2 gain of function led to activation of the bile salt export pump (BSEP) promoter, a well-characterized FXR response. BSEP activation by PLD2 could be blocked by abrogating either PKCζ or FXR signaling. PLD2 loss of function led to a reduction in BSEP promoter activity. In addition, a variety of proteins that are activated by FXR, including BSEP, were reduced in HepG2 cells treated with PLD2 siRNA. Similar effects were observed in freshly isolated human hepatocytes. Activation of BSEP by FIC1 gain of function was blocked when PLD2 but not PLD1 was silenced. Overexpression of wild-type but not Byler mutant FIC1 led to an increase in membrane associated PLD activity. An intermediate level of activation of PLD activity was induced when a benign recurrent intrahepatic cholestasis FIC1 mutant construct was expressed. These studies show that FIC1 signals to FXR via a signaling pathway including PLD2 and PKCζ.     

Bile acid and sterol metabolism with combined HMG-CoA reductase and PCSK9 suppression

Proprotein convertase subtilisin-kexin-9 (PCSK9) inhibition markedly augments the LDL lowering action of statins. The combination is being evaluated for long-term effects on atherosclerotic disease outcomes. However, effects of combined treatment on hepatic cholesterol and bile acid metabolism have not yet been reported. To study this, PCSK9-Y119X mutant (knockout) and wild-type mice were treated with or without atorvastatin for 12 weeks. Atorvastatin progressively lowered plasma LDL in each group, but no differences in liver cholesterol, cholesterol ester, or total bile acid concentrations, or in plasma total bile acid levels were seen. In contrast, atorvastatin increased fecal total bile acids (∼2-fold, P < 0.01) and cholesterol concentrations (∼3-fold, P < 0.01) versus controls for both PCSK9-Y119X and wild-type mice. All 14 individual bile acids resolved by LC-MS, including primary, secondary, and conjugated species, reflected similar increases. Expression of key liver bile acid synthesis genes CYP7A1 and CYP8B1 were ∼2.5-fold higher with atorvastatin in both strains, but mRNA for liver bile acid export and reuptake transporters and conjugating enzymes were not unaffected. The data suggest that hepatocyte cholesterol and bile acid homeostasis is maintained with combined PCSK9 and HMG-CoA reductase inhibition through efficient liver enzymatic conversion of LDL-derived cholesterol into bile acids and excretion of both, with undisturbed enterohepatic recycling.     

妊娠期肝内胆汁淤积症患者血清总胆汁酸水平与炎症因子、Th17/Treg平衡及母婴结局的关系研究

摘要 目的：分析妊娠期肝内胆汁淤积症（ICP）患者血清总胆汁酸（TBA）水平与炎症因子[肿瘤坏死因子-α（TNF-α）、白介素-12（IL-12）、白介素-6（IL-6）]、Th17/Treg平衡及母婴结局的关系。方法：选取2018年1月-2020年12月期间我院收治的ICP患者94例为ICP组,另选取同期来我院产检的90例正常妊娠妇女为对照组,对照组孕妇于体检当日、ICP组于入院次日在早晨空腹状态下抽取外周静脉血,应用流式细胞仪测定Th17、Treg细胞比率,采用全自动生化分析仪对血清TBA水平进行检测与分析,采用酶联免疫吸附法检测TNF-α、IL-6、IL-12水平。根据ICP孕妇血清TBA水平分为低TBA组（<40 μmol/L,58例）与高TBA组（≥40 μmol/L,36例）,观察两组围生儿结局、产妇妊娠结局、新生儿并发症发生率。结果：ICP组的TBA、TNF-α、IL-6、IL-12、Th17、Th17/Treg均高于对照组,Treg低于对照组（P<0.05）。低TBA组剖宫产率低于高TBA组,阴道自然分娩率高于高TBA组（P<0.05）,两组阴道助产率组间对比差异无统计学意义（P>0.05）。低TBA组胎儿宫内发育迟缓率、胎儿宫内窘迫率低于高TBA组（P<0.05）。两组新生儿窒息率、围生儿死亡率组间对比差异无统计学意义（P>0.05）。低TBA组新生儿并发症总发生率低于高TBA组（P<0.05）。Pearson线性相关分析结果显示,血清TBA与TNF-α、IL-6、IL-12、Th17/Treg比值呈正相关（P<0.05）。结论：ICP患者的TBA水平越高,母婴不良结局发生率越高,此外,ICP患者具有明显的炎症反应和Th17/Treg平衡情况,促进疾病进展。     

The histidin-loop is essential for transport activity of human MDR3. A novel mutation of MDR3 in a patient with progressive familial intrahepatic cholestasis type 3

Experimental evidence has been provided that a histidine-loop within the nucleotide binding domain of ABC transporter is essential for efficient function of this class of transporter proteins. Here we report the first patient with a mutation of the putative histidine-loop of a human ABC transporter, the multi drug resistance protein 3 (MDR3). The patient presented at the age of 4years with a history of severe pruritus, elevated serum gamma-glutamyltransferase and bile acid levels since several years suggesting the diagnosis of progressive familial intrahepatic cholestasis type 3 (PFIC-3) due to defects in MDR3. Liver biopsy demonstrated an apparently normal MDR3 expression, however, genetic analysis revealed a novel homozygous mutation in the ABCB4 gene (c.3691C>T) in the patient. This mutation was associated with a change of histidine to tyrosine at amino acid position 1231 of MDR3 (p.H1231Y). As shown by sequence alignment, this amino acid corresponds to the highly conserved histidine of the "H-loop", which is critical for ATP-hydrolysis, suggesting an essential role of histidine 1231 of human MDR3.