Study on the mechanism of an experimental immunological intrahepatic cholestasis model.

Tuberculin-sensitized guinea pigs were intravenously injected with heat-killed Propionibacterium acnes followed by an intravenous injection of purified protein derivatives 7 day later, resulting in the induction of intrahepatic cholestasis. Using this experimental model, the following results were obtained: (1) Both uptake and release of bile acid were inhibited in the hepatocytes prepared from the cholestasis guinea pigs. (2) The results of the erythritol clearance method indicated that the decrease in bile flow observed in the cholestasis guinea pigs was mostly attributable to the reduced bile excretion from the canaliculi. (3) The decrease in the formation of bile acid independent bile flow was the cause of the decrease in bile flow observed in the cholestasis guinea pigs. (4) There was no change in the permeability of the interhepatocellular tight junction in the cholestasis guinea pigs.     

Low protein diets potentiate lithocholic acid-induced cholestasis in rats.

Earlier studies showed that low protein diets (LPD) reduce bile flow and bile acid secretion. We therefore examined the effect of LPD on lithocholic acid (LCA)-induced intrahepatic cholestasis. Female Sprague-Dawley rats were fed LPD (8% casein) soon after weaning for 4 or 12 wk, and then were injected intravenously with a single dose of LCA (4 mumol/100 g body wt). Bile was collected for 30-min periods, and bile flow as well as biliary lipid secretory rates were measured. Bile acid metabolism was also studied and the results were compared with those obtained in rats fed an adequate protein diet (26% casein). The LPD produced significantly lower bile flow and bile acid secretion, which were attributed to a reduced bile acid pool and a reduction in synthesis. They also enhanced the LCA-induced decline in bile flow, and rate of biliary output of total bile acids, phospholipids and cholesterol. The LPD were also associated with impaired LCA secretion in bile and increased retention in plasma and liver. Studies of LCA metabolism in rats fed a LPD indicated lower hepatic LCA hydroxylation, a greater percent contribution of glyco conjugates and lower levels of tauro conjugates. The present findings suggest that the reduced bile acid pool size, diminished LCA excretion and biotransformation to less toxic bile acids may explain the greater cholestasis in LPD-fed rats.     

Hyperalimentation-associated jaundice: an example of a serum factor inducing cholestasis in rats

A patient receiving total parenteral nutrition (TPN) at home following emergency resection of the small intestine was studied over a two year interval. Cholestatic jaundice developed after 6 months. A factor in serum was found to produce cholestatic changes in the bile flow of rats on intravenous infusion. Normal human serum and saline infusion did not produce this cholestasis. Endotoxin infusion in the rat produced a similar impairment in bile flow. The hypothesis was proposed that endotoxin might be an occult factor contributing to cholestasis in this case. An antiserum prepared to an endotoxin isolated from a sequestered E. coli infection in this patient, ameliorated the cholestatic effects of the patients' serum in rats. The possible role of endotoxin in the cholestasis of the TPN-induced jaundice in this patient is presented and discussed.     

UDCA 联合SAMe治疗妊娠期肝内胆汁淤积症的 Meta分析

目的系统评价熊去氧胆酸（UDCA）联合腺苷蛋氨酸（SAMe）与单用UDCA对改善妊娠期肝内胆汁淤积症（ICP）孕妇生化指标及瘙痒症状的效果。方法利用计算机检索2003年至今维普、万方、中国学术期刊网全文数据库（CNKI）、中国生物医学文摘数据库（CBM）、美国国立数据库（PUBMED）、荷兰医学文献数据库（EMBASE）等,查找关于UDCA联合SAMe与单用UDCA治疗ICP的随机对照研究文献,筛选后进行质量评价并提取数据,用RevMan5．2软件进行Meta分析。结果与单用UDCA相比,UDCA联合SAMe改善孕妇瘙瘁症状明显,降低血清总胆汁酸、总胆红素、谷丙转氨酶、谷草转氨酶效果显著。结论UDCA联合SAMe治疗ICP在改善孕妇瘙痒症状和血清生化指标方面明显优于单用UDCA。     

Effects of ursodeoxycholic acid on intrahepatic cholestasis

Ursodeoxycholic acid (UDCA) was administered to 16 intrahepatic cholestasis patients with severe jaundice, and its clinical effects were studied. As a result, it was remarkably effective in 6 patients, significantly effective in 5 patients, slightly effective in 2 patients and unchanged in 3 patients. As for the dose, when 600 mg/day was administered, it was effective in all patients, but even when only 150 mg/day was administered, it was effective in one patient (50%). Duration of treatment was 15 to 177 days with a mean of 55.3 days. These results suggested that while there is no adequate treatment for intrahepatic cholestasis with severe jaundice, UDCA should be considered as a possible method of treatment.     

熊去氧胆酸治疗婴儿胆汁淤积型巨细胞病毒性肝炎的临床评价

目的：观察熊去氧胆酸（UDCA）治疗婴儿胆汁淤积型巨细胞病毒性（CMV）肝炎的疗效及安全性。方法：40例患儿按随机数字表法分为UDCA治疗组20例与对照组20例,两组病例均予抗病毒、保肝及综合治疗。治疗组在此基础上加用UD,观察临床表现及肝生化指标,判断药物疗效。结果：治疗2周后观察患儿氨酸ALT、总胆红素TBIL、总胆汁酸TBA、碱性磷酸酶AKP、谷氨酰转肽酶GGT水平均较治疗前下降,差异具有统计学意义（P〈0.05）。加用UDCA治疗组TBA、TBIL下降明显,优于对照组（P〈0.05）。结论：对于婴儿胆汁淤积型CMV肝炎,辅助应用UDCA,促进胆汁酸排泄、加速黄疸消退,改善肝功能,且无明显不良反应,安全有效,值得推广。     

妊娠期肝内胆汁淤积症胎儿宫内缺氧机制的研究进展

妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)是发生在妊娠中、晚期的一种妊娠特有并发症,以皮肤瘙痒、胆汁酸升高和肝功能异常为主要临床表现.此妊娠并发症孕产妇预后良好,但可导致胎儿早产、羊水胎粪污染、胎儿宫内窘迫,甚至胎死宫内等严重妊娠结局.因此,研究妊娠期肝内胆汁淤积症胎儿宫内缺氧的机制对围生儿预后至关重要.本文就妊娠期肝内胆汁淤积症胎儿宫内缺氧机制的研究进展,综述如下.     

Bile formation and cholestasis

Transport proteins in hepatocytes and bile duct epithelium mediate uptake and secretion of cholephilic compounds in the liver and are involved in bile formation. Many of these proteins have recently been cloned and characterized and appear to belong to large gene families. Apart from the liver these proteins are expressed in the blood-brain barrier, placenta, kidneys, lungs, intestine and seminiferous tubules. Prokaryotes and yeasts contain similar proteins. In cancer cells they are involved in multidrug resistance. Some genetic cholestatic liver diseases, including progressive familial intrahepatic cholestasis, Dubin-Johnson syndrome, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy result from mutations in transport protein genes. These proteins also play a role in drug-induced liver disease and in primary biliary cirrhosis. Cyclosporine and oestradiol (glucuronide) for instance inhibit bile salt export protein (BSEP).     

The pathogenesis of cholestasis

How does cholestasis develop when there is no obvious obstruction, destruction, or malformation of bile ducts? Recent findings on bile formation and flow are reviewed, and two models of intrahepatic cholestasis are presented: one of rapid onset, which is bile acid induced, and the other of slow onset, which is estrogen induced. Potential clinical correlations are discussed.     

Effect of a low protein diet on bile flow and composition in rats

The effect of feeding a low protein (LP) diet on bile flow and biliary lipid and protein secretion was studied with young female rats. Animals fed a 8% protein diet (LP) for 4, 8 and 12 wk had a significantly lower bile flow and a lower biliary bile acid and protein secretion rate compared with rats fed a 26% protein (normal) diet (NP). The bile acid-independent fraction of bile flow was significantly increased. The slope of the regression line to zero bile acid was markedly smaller in the LP than in the NP group, indicating lower bile acid-dependent bile flow. Biliary phospholipid and cholesterol secretion rates were significantly higher in the LP than in the NP group, demonstrating an uncoupling between bile acid and lipid secretion at the low rates of bile acid secretion. The percentage increase for these parameters was of similar magnitude (30%). Absolute concentrations of bile acid, phospholipid and cholesterol were significantly higher in LP-fed rats than in NP rats, while relative concentration of bile acid was lower and those of cholesterol and phospholipid were higher. Analysis of biliary bile acids showed that the percent contribution of chenodeoxycholic acid and of deoxycholic acid increased significantly in the LP-fed rats, while that of cholic acid decreased. These data indicate that the lower bile flow in the rats fed LP can be attributed to lower bile salt-dependent flow associated with significantly lower choleretic potency of bile acids secreted.     

Biliary excretion of choleretically active cinnamic acid derivatives in the rat

Concerning the well-known choleretic effect of ferulic acid, we made further investigations on biliary excretion, metabolism and bile flow after application of ferulic acid and related compounds. In anesthesized bile duct cannulated male Wistar-rats, we studied the biliary excretion of the following 14-C labelled cinnamic acid compounds: caffeic acid (CA), ferulic acid (FA), m-coumaric acid (mCA), p-coumaric acid (pCA), isoferulic acid (IFA), p-methoxycinnamic acid (pMCA), 3,4-dimethoxycinnamic acid (DMCA), and 3,4,5-trimethoxycinnamic acid (TMCA). These compounds were given intraduodenally (128-384 mumoles/kg b. wt.). All of the tested compounds were excreted to some extent in bile, giving a bile to the serum conc. ratio greater than 1. The radioactivity excreted by bile within 2 hours (as percent of the given dose) was about 20% in the case of FA, IFA, DMCA, and TMCA, about 8% for pMCA, and less than 5% for CA, mCA and pCA. The biliary excretion increased in a dose-dependent manner only after FA and IFA, but not after application of the other compounds.     

雌激素受体α对胆汁酸转运相关基因的调控及其与孕鼠肝内胆汁淤积症发生的相关性

目的探讨雌激素受体α(estrogen receptorα,ERα)对参与调节胆汁酸转运相关的基因,如法尼醇X受体(farnesoid X receptor,FXR)、钠离子-牛磺胆酸共转运蛋白(sodium taurocholate co-transprorting polypeptide,NTCP)、胆盐输出泵(bile salt export pump,BSEP)的调控作用及其对孕鼠肝内胆汁淤积发生的影响。方法将40只SPF级SD孕鼠随机均分为4组。自孕第15 d起,对照组颈部皮下注射精制植物油2.0 m L/kg·d;低、中、高剂量组分别皮下注射17α-乙炔雌二醇1.0 mg/kg·d、1.25 mg/kg·d、1.5 mg/kg·d。于妊娠第21 d采血2 m L,后采用颈部脱臼法处死,提取母鼠肝脏行活体组织学检查。检测各组孕鼠血清中的生化指标及肝脏组织中各目的蛋白和mRNA表达量。结果生化指标:低、中、高剂量组孕鼠各蛋白表达水平明显高于对照组,差异有统计学意义(P0.05),低、中、高剂量组组间比较,差异有统计学意义(P0.05);蛋白表达及mRNA的表达水平:ER在对照组、低剂量组、中剂量组、高剂量组的表达量依次升高,而FXR、NTCP、BSEP在对照组、低剂量组、中剂量组、高剂量组的表达量依次降低,各组目的基因表达量与对照组比较,差异均有统计学意义(P0.05)。结论随着雌激素剂量的增加,ERα表达水平升高,而FXR、NTCP、BSEP表达水平均降低,提示胆汁酸代谢转运功能降低,可能为雌激素诱导孕鼠肝内胆汁淤积的发生机制之一。     

Differentiation and Management of the Patient with Jaundice

The challenge is to determine whether the impairment of liver function affects primarily bilirubin or bile salts excretion; differentiating the jaundiced patient according to whether cholestasis, in its true sense of bile standstill, is present or not is often rewarding. The problem may be compounded by the appearance of jaundice and/or cholestatic symptoms as complications of extrahepatic primary diseases.     

New molecular features of cholestatic diseases of the liver

Hepatic uptake and biliary excretion of bile salts and non-bile salt organic anions is mediated by specific transport proteins located at the basolateral and canalicular membranes of hepatocytes. Several hepatobiliary transport systems have been identified and cloned over the past years. This development has facilitated molecular biological and genetic analyses of these transporters in experimental cholestasis and human cholestatic liver diseases. Evidence now exists that decreased or even absent expression of hepatobiliary transport systems may explain impaired transport function resulting in hyperbilirubinemia and cholestasis. This review summarizes the molecular defects in hepatocellular membrane transporters associated with hereditary and acquired forms of cholestatic liver diseases. The increasing information on the molecular regulation of hepatobiliary transport systems should bring new insights into the pathophysiology and treatment of human cholestatic liver diseases.     

腺苷蛋氨酸预防大鼠全肠外营养并发的胆汁淤积

目的：观察Ｓ－腺苷－Ｌ－蛋氨酸（ＳＡＭｅ）对大鼠ＴＰＮ胆汁淤积的预防效果,并比较胆汁中胆盐的变化。方法：１８只ＳＤ大鼠随机分为三组,对照组,ＴＰＮ组,ＴＰＮ＋ＳＡＭｅ组,每组各６只,后两组均ＴＰＮ支持５天,然后插管收集胆汁,测量胆汁流量,采血检测血清总胆酸（ＳＴＢＡ）、ＧＧＴ、ＡＬＴ,ＡＫＰ水平,观察光镜,电镜下肝的病理变化,检测胆汁中胆盐含量。结果：ＴＰＮ组出现胆汁流下降,ＳＴＢＡ,ＧＧＴ水平升     

妊娠合并肝内胆汁淤积症疗效分析

目的：探讨妊娠合并肝内胆汁淤积症42例临床疗效。方法：分析本院收治的妊娠合并肝内胆汁淤积症患者42例的临床资料,妊娠合并肝内胆汁淤积症患者给予针对性治疗的22例患者作为观察组,其余20例不进行干预作为对照组。结果：观察组治疗后血清总胆红素、谷丙转氨酶、血清胆汁酸均较治疗前明显改善,同时观察组分娩孕周、胎儿窘迫、羊水污染、新生儿窒息、早产、围生儿死亡、新生儿体重均优于对照组,差异有统计学意义（P〈O．05）。结论：妊娠合并肝内胆汁淤积症采取相应的对症治疗,可明显改善临床症状,提高妊娠结局的质量,值得临床推广应用。     

腺苷甲硫氨酸对感染大鼠全肠外营养胆汁淤积的预防

目的：观察S－腺苷－L－甲硫氨酸（S－Adenothyl-L-methionine,SAMet)对感染大鼠TPN淤胆的预防效果。方法：18只体重240－280g的SD雄性大鼠随机分为三组；对照组，感染＋TP组，感染＋TPN＋SAMet组，每组各6只，后两组均结扎盲肠致感染并持续TPN支持5天。SAMet按80mg/(kg.d)加入营养液中。实验结束，胆总管插管收集胆汁，测流量，采用检测血清总胆酸（STBA）、GGT、ATLT、AKP水平，光镜、电镜下观察肝病理变化，HPLC法检测胆汁中八种结合胆直总胆盐含量。结果：感染＋TPN组与对照组比较出现胆汗流下降，STBA、GGT、AKP水平升高，病理检查见肝组织脂肪浸润、毛细胆管扩张及胆栓；而感染＋TPN＋SAMet组较感染＋TPN组胆汁流升高，STBA、GGT、ALT、AKP水平均显著下降，肝 正常或病理改变明显减轻。胆汁胆直部仅个别胆盐有差异，其余绝大部分胆盐间无显著差异。结论：在感染大鼠实施TPN时给予SAMet可有效预防TPN胆汁淤积的发生，为临床上有不停止TPN的情况下预防淤胆的发生提供了一种新的措施。     

Biliary steroid excretion in rats fed soybean protein and casein or their amino acid mixtures

Male Wistar rats were fed 1% fat, cholesterol-free semipurified diets containing soybean protein isolate and casein or amino acid mixtures simulating these proteins for 28-30 days. The animals then underwent surgery for biliary diversion, and bile was collected for 2 hours. The rate of bile flow was not influenced by the type of dietary protein. The concentration and output of biliary cholesterol in rats fed soybean protein were significantly higher than in those fed casein, while biliary bile acid excretion was comparable. The group given the soy protein-type amino acid mixture also tended to excrete more biliary cholesterol relative to the casein-type amino acid mixture, although the difference was not significant, while biliary bile acid output was comparable. When 5% fat diets containing 0.5% cholesterol were given to rats, concentrations of both biliary cholesterol and bile acid were elevated significantly on a vegetable protein diet. In these experiments, there was a significant negative correlation between serum cholesterol and biliary cholesterol levels. Stimulation of the biliary excretion of cholesterol seems at least relevant to the cholesterol-lowering action of soybean protein.     

茵陈利胆汤结合熊去氧胆酸在ICP患者中的疗效分析

目的 探讨茵陈利胆汤结合熊去氧胆酸在妊娠期肝内胆汁淤积症(ICP)患者中的疗效.方法 选择2014年1月至2016年12月在广州医科大学附属第五医院产科就诊的92例ICP患者为研究对象,按照随机数字表法分为观察组与对照组,每组46例.对照组口服熊去氧胆酸片进行治疗,300mg/次,3次/日,7日为1疗程.观察组在对照组基础上加用茵陈利胆汤,1剂/日,用水煎服,分2次服用,7日为1疗程.对比两组患者治疗后疗效、皮肤瘙痒情况、总胆汁酸、天冬氨酸转氨酶、丙氨酸氨基转移酶、肝胆酸水平及围产儿结局.结果 观察组患者的治疗总有效率为89.13%,显著高于对照组的71.74%,差异有统计学意义(χ2=4.372,P<0.05).治疗前两组患者的皮肤瘙痒评分、总胆汁酸、肝胆酸、天冬氨酸转氨酶、丙氨酸氨基转移酶水平(t=0.224~0.675,均P>0.05)治疗后两组患者上述指标均显著降低(t=2.986~6.032,均P<0.05),但观察组治疗后均显著低于对照组(t=2.490~3.847,均P<0.05).观察组胎儿窘迫、早产、新生儿窒息发生率均显著低于对照组(χ2值分别为4.342、4.789、7.939,均P<0.05).结论 茵陈利胆汤结合熊去氧胆酸治疗ICP疗效、安全性均显著优于单独使用熊去氧胆酸.     

妊娠期肝内胆汁淤积症51例临床分析

目的 了解妊娠期肝内胆汁淤积症的临床表现、妊娠结局.方法 对住院治疗的妊娠期肝内胆汁淤积症51例,回顾分析临床表现、治疗及结局.结果 38例有皮肤瘙痒表现,占74.5%.49例(96.1%)血清总胆汁酸升高.经过治疗,49例(96.1%)至37周剖宫分娩.新生儿窒息2例(3.9%).结论 妊娠期肝内胆汁淤积症对母儿危害较大,但通过积极有效的治疗,预后良好.