CHANGES IN LIVER BLOOD FLOW WITH DEVELOPMENT OF BILIARY OBSTRUCTION IN THE RAT1

As well as causing retention of biliary secretory products, bile duct obstruction is associated with other hepatic and systemic effects which are poorly understood. These latter changes contribute to the increased morbidity and mortality associated with surgery for biliary obstruction. This study examines the changes in liver blood flow occurring after common bile duct (CBD) ligation in the belief that relative hepatic ischaemia may contribute to dysfunction. A new method for measuring liver blood flow (LBF) based on the clearance of ¹³³Xe from the liver following injection into the portal vein is described. With this new development, serial measurements of LBF can be performed in the conscious, unfasted rat. With the development of jaundice, a highly significant reduction in LBF is seen which is first evident 36 hours after CBD ligation. By the third day after ligation, LBF is only 54% of the control value. No fall in LBF is seen in rats subjected to sham ligation. The mechanism for the reduction in LBF is uncertain, but the delayed onset makes any reflex autonomic reaction unlikely.     

The pathomorphology of the liver after unilateral hepatic duct obstruction with laboratory-chemical observations of the course in the dog

In an experimental study the morphological and functional changes of the liver with unilateral hepatic duct obstruction were investigated over a period of 13 months. In 4 series different parts of the liver were excluded of the bile drainage by hepatic duct ligation after cholecystectomy (group I = 25%, group II = 50%, group III 75%, group IV = 100% of the liver, series V = control group was cholecystectomy only. The clinical outcome, biochemical parameters, liver biopsy were examined regularly. Bacteriologic investigation of the bile and hepatic flow measurement were performed at the beginning and at the end of the study. RESULTS: The clinical symptoms were discrete and the biochemical parameters showed a typical course. After 6 weeks, atrophy of the excluded liver with contralateral compensatoric hypertrophy was found. The microscopic correlation was the secondary sclerosing cholangitis (SSC). After 6 weeks, a concentric periductal fibrosis was to be observed in the periportal area. After 12 weeks, bile duct vanishing with persistence of the arteries and veins was found. After 36-48 weeks, biliary cirrhosis and total destruction of the liver parenchyma was found respectively. Simultaneously a chronic disturbance of the hepatic perfusion was seen. It was caused by a perivenous fibrosis of the terminal vein with obliteration of the lumen by endangiitic proliferations and cavernous transformation. The genesis of SSC seemed not be be influenced by bile contamination. The ligated as well as the unligated bile ducts were infected in 20-50% only. There was no difference in the liver specimens with sterile or contaminated bile. The hepatic flow measurement showed a reduction of the portal blood flow and a rise of the arterial flow depending on the amount of the excluded liver. A better understanding of the pathophysiological sequelae of the unilateral hepatic duct obstruction suggests that the drainage by surgical or radiological methods may not invariably be necessary.     

胆道梗阻肝细胞膜Na+/K+ATP酶的变化

目的动态观察在胆道梗阻和梗阻缓解过程中,肝细胞膜Na+/K+ATP酶活性变化的规律。方法对130只胆道梗阻大鼠模型的260份样本进行组织化学染色,结合免疫电镜方法,在肝细胞膜上染色定位Na+/K+ATP酶,计算机图像分析测定,半定量比较肝细胞膜Na+/K+ATP酶活性。结果Na+/K+ATP酶广泛存在于肝细胞膜上,但其活性(相对灰度比值)在肝细胞血窦面、肝细胞间面和肝细胞毛细胆管面呈不均匀分布,分别为107.60±16.64、74.40±9.37、90.30±8.04。反映了肝细胞分泌胆汁的正常极性。Na+/K+ATP酶活性在胆道梗阻和梗阻缓解过程中随着胆红素水平的升高或降低而发生变化,并且随着梗阻和缓解的时间延长而明显下降或改善。在梗阻14d时,分别降为84±10、60±7、65±15;在梗阻14 d缓解1 d时,Na+/K+ATP酶活性分别为86±14、62±6、68±19,而在缓解7 d时其活性分别恢复为96±8、65±6、85±7。结论胆道梗阻对肝细胞膜Na+/K+ATP酶活性的影响可能与胆道梗阻时肝细胞代谢胆红素障碍有关。     

Experimental study on the interruption of hepatic blood flow in obstructive jaundice, with special reference to the causes of death and prolonged jaundice after biliary decompression

The purpose of this investigation was to elucidate the influence of interruption of the hepatic blood flow on survival and on prolonged jaundice after biliary decompression in dogs with obstructive jaundice. There were three experimental groups. Two or three weeks after inducing obstructive jaundice by ligation of the common bile duct with cholecystectomy, the hepatic artery (group A), portal vein (group B) or both (group C) were interrupted for various intervals, with antibiotics administration. Biliary decompression was simultaneously performed with choledochoduodenostomy. The one week survival rate after the interruption of hepatic blood flow was more than 60% at 2 and 1 hours in group A, 20 and 10 minutes in group B, 10 and 5 minutes in group C at two and three weeks after biliary obstruction, respectively. Necrosis more than 50% of the liver was observed in early death cases. Edema and stasis in the bile canaliculi were markedly observed histologically in survivors in groups A and C, accompanied with significant elevations of serum T. Bil and GPT. The changes were greater in cases with longer periods of jaundice. In obstructive jaundice, hepatic artery occlusion causes hepatic necrosis, in spite of antibiotics administration, and may induce prolonged jaundice after biliary decompression. As an indicator of the prognosis, the serum total bile acid value was useful.     

梗阻性黄疸-选择性胆管外引流大鼠模型的建立

目的建立梗阻性黄疸-选择性胆管外引流（约占30%肝脏体积）动物模型,了解其对胆汁分泌及肝功能改善的影响,为肝门部胆管癌减黄实验及临床研究提供参考。方法采用结扎切断SD大鼠左中叶肝胆管及胆总管预制外引流管10d的方法,制作大鼠选择性胆管外引流模型,在引流的0、1、4、7、10、14d收集胆汁及检测肝功。结果成功建立了大鼠完全梗阻性黄疸部分肝脏外引流的模型并观测到其对胆汁分泌及肝功能改善的影响。结论与梗阻性黄疸全肝外引流模型相比,梗阻性黄疸约30%肝脏外引流能够改善肝功能,而且可以增加预保留肝的功能代偿。     

一氧化氮和内皮素-1在淤胆性肝纤维化中的作用机制

目的: 探讨一氧化氮(NO)和内皮素-1(ET-1)在淤胆性肝纤维化中的作用机制.方法: 将Wistar大鼠48只,随机分成对照组、胆总管结扎组和胆总管结扎+内毒素拮抗剂组,观察术后3 d、7 d、14 d和21 d血浆内毒素、N0和ET-1水平,肝脏结构和功能的变化.结果: 胆总管结扎致胆汁淤积后,随着血浆内毒素水平升高,NO和ET-1水平相应上升,血清AST和ALT也明显升高.肝纤维化程度随梗阻时间逐渐加重,电镜下见肝窦变窄,Disse间隙增宽,内有大量胶原纤维沉积,肝筛的数量和直径均明显减少.应用乳果糖能部分逆转肝脏功能和结构的病理改变.结论: N0和ET-1在淤胆性肝纤维化进程中具有重要作用,二者可能是通过肝筛而发挥作用的.     

The importance of the hepatic artery in rat liver transplantation

The hepatic artery is important in preventing biliary ischemia and obstruction after bile duct reconstruction or orthotopic liver transplantation in the rat. A technique of orthotopic liver transplantation in the rat with reestablishment of the arterial inflow is described, suitable for studies in immunology and preservation. Reestablishment of both venous and arterial inflow is required to minimize biliary complications. General survival, hepatic cellular function, and biliary drainage are all improved by rearterialization. In all these features, the rat illustrates characteristics applicable to human liver transplantation. The vital requirement of the adequacy of blood supply to the bile duct in liver transplantation surgery in all species is highlighted by these findings, which indicate clearly the importance of an arterial blood supply in rat liver transplantation and bile duct surgery.     

蛙皮素对胆道梗阻大鼠肝脏氧化应激的影响

目的探讨蛙皮素对胆道梗阻大鼠肝脏氧化应激的影响。方法40只Wistar雄性大鼠随机分成4组:正常组、假手术组、黄疸组、蛙皮素组。术后第10天,下腔静脉检测血ALT、LPS水平,肝脏表达SOD、MDA、XOD、GSH衡量氧化应激状态,光镜下观察肝脏组织结构。结果胆道梗阻下腔静脉ALT、LPS值升高,肝脏SOD、GSH表达减少,MDA、XOD表达增加,组织炎性细胞浸润较多,肝脏高氧化应激。蛙皮素注射10d,血清ALT、LPS水平及组织炎性细胞浸润减少,肝脏高氧化应激状态降低。结论蛙皮素降低胆道梗阻大鼠肝脏氧化应激,其机制可能与肝脏蛋白激酶C、LPS水平及炎性细胞浸润有关。     

An unusual case of jaundice: Biliary tumor thrombus in fibrolamellar hepatocellular carcinoma

BackgroundFibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and unique variant of hepatocellular carcinoma (HCC) whose presentation remains inadequately described. We present a resectable case of FL-HCC which involved tumor thrombus of the common bile duct.PresentationA 27 year-old male presenting with jaundice, abdominal pain, vomiting, hepatic dysfunction and hyperbilirubinemia was found to have a large liver mass and lymphadenopathy on preoperative imaging. A right hepatectomy with perihepatic lymph node dissection and cholecystectomy was performed. Intraoperative cholangiogram demonstrated common bile duct (CBD) obstruction. CBD exploration revealed biliary tumor thrombus relieved with biliary thrombectomy.DiscussionFL-HCC can initially present with invading obstructing biliary tumor thrombus of the CBD causing jaundice.ConclusionPreoperative surgical approach should consider CBD exploration on an individual basis for underlying obstructive biliary tumor thrombus.     

Changes of hepatic blood flow and intrahepatic microvascular bed in rats with chronic biliary obstruction]

The effective hepatic blood flow (EHBF) and intrahepatic microvascular bed (IMB) of rats were studied with hydrogen clearance and India ink perfusion 1, 2, 3 weeks after common bile duct ligation (CBDL). The EHBF decreased significantly in all 3 CBDL groups, compared to control (P < 0.0001). There was no significant difference among CBDL groups (P > 0.05). In a given group no significant difference was noted between the blood flow of the left lateral lobe and that of the middle lobe. The IMB was destroyed severely in all CBDL groups. It was concluded that when chronic biliary obstruction developed the EHBF decreased significantly because of shrinkage of IMB resulting from extensive fibrosis of the liver, and necrosis of liver cells.     

Development and reversal of endotoxemia and endotoxin-related death in obstructive jaundice

Gut-derived endotoxemia has been implicated in postoperative complications in patients with jaundice. It is thought that absence of bile in the gut predisposes to portal absorption of endotoxin and endotoxemia is reversed by oral bile salt replacement or internal biliary drainage and return of bile to the gut, but not by external drainage. We believe that the importance of gastrointestinal bile flow has been overestimated and biliary obstruction and the integrity of hepatocyte and Kupffer cell function are more important in the development and reversal of endotoxemia. In experiment 1, serum endotoxin concentrations were measured in control rats (n = 10) after choledochovesical fistula (n = 15) and bile duct ligation (n = 15) and after relief of biliary obstruction by internal drainage (choledochoduodenostomy; n = 8) and sterile external drainage (choledochovesical fistula; n = 8), with a quantitative limulus assay. In experiment 2, mortality rates were measured in similar groups 48 hours after administration of oral endotoxin (5 mg/100 gm) and intravenous lead acetate (5 mg/100 gm). Bilirubin levels were elevated in bile duct ligation (192 +/- 13 mumols/L) compared with control animals and those with choledochovesical fistula, internal drainage, and external drainage (10.6 +/- 1.5 mumols/L). In experiment 1, significant portal endotoxemia and systemic endotoxemia occurred in bile duct ligation (portal, 130.4 +/- 12.9 pg/ml; systemic, 91.8 +/- 11.0 pg/ml) but not in choledochovesical fistula (portal, 49.3 +/- 17.1 pg/ml; systemic, 27.2 +/- 11.5 pg/ml). Relief of obstruction by both internal and external drainage reversed endotoxemia. In experiment 2, significant death occurred in bile duct ligation (13 of 15) but not in choledochovesical fistula (3 of 15), and relief of obstruction by both internal and external drainage prevented death. These results confirm that biliary obstruction is a more important factor than is gastrointestinal bile flow in the development and reversal of endotoxemia.     

Impaired bacterial clearance and trapping in obstructive jaundice.

Sepsis is a major cause of mortality in patients with common bile duct obstruction. To define possible contributing factors to this phenomenon, this study evaluates the effect of biliary obstruction on the intravascular clearance and organ trapping of viable Escherichia coli using a rat model. Adult male Sprague-Dawley rats were placed in three groups: Group I controls had sham operation, Group II had division and ligation of common bile duct (CDL), and Group III underwent splenectomy. At 21 days following operation 10(9) radiolabeled E. coli were injected intravenously. At varying intervals after infusion, blood samples were obtained for clearance study. At 10 minutes, bacterial distribution in the liver, spleen, kidneys, and lungs was determined (expressed as the mean percentage of injected viable E. coli). Intravascular clearance was similar in all groups. There was a significant decrease in the trapping of bacteria by the liver of CDL rats 14.5% +/- 4.95 (vs. control = 70.0% +/- 13.3) (p less than 0.005). A significant increase of bacterial trapping by the lung was observed in the CDL animals: 63.1% +/- 7.06 (vs. controls 1.4% +/- 0.82) (p less than 0.005). There was no significant change in bacterial localization in splenectomized rats. These data suggest that biliary obstruction decreases hepatic phagocytosis and increases pulmonary localization of viable E. coli. As the Kupffer cells of the liver are usually effective in removal of blood borne bacteria, this phagocytic dysfunction may contribute to the increased susceptibility to infection noted in instances of biliary obstruction.     

Hepatic recovery after biliary decompression of experimental obstructive jaundice

Obstructive jaundice was produced in 11 dogs by common bile duct ligation for 4 weeks, then biliary decompression was performed by bilioenteric anastomosis. Animals were regularly studied over the 2 months after decompression by the following methods: (1) serum biochemistry was monitored; (2) light microscopic changes in serial liver biopsies were graded; (3) the respiratory characteristics of isolated hepatic mitochondria, obtained by open liver biopsy, were studied using an oxygen micro-electrode system; (4) in vivo handling of an hepatobiliary imaging agent (diisopropyl iminodiacetic acid) was studied by dynamic liver scintiscanning. None of these liver assessments were normalized after 7 to 10 days of biliary decompression. Our study suggests that biliary decompression of patients with extrahepatic biliary obstruction requires long periods of time to enable major recovery of the abnormal liver function induced by biliary obstruction.     

Biliary obstruction reduces hepatic killing and phagocytic clearance of circulating microorganisms in rats

Septic complications are common in patients with biliary obstruction. This is thought to be related, in part, to dysfunction of the hepatic reticuloendothelial system (RES). It has been reported that nearly 80% of circulating microorganisms are phagocytosed and killed within the liver and that clearance of circulating pathogens is significantly impaired in patients with jaundice. However, the effect of biliary obstruction specifically on phagocytic killing within the liver is less well described. Therefore this study was designed to quantify the effect of biliary obstruction, simultaneously and discriminately, on two important components of hepatic RES function (phagocytosis and phagocytic killing). Rats were divided into three experimental groups: control, sham, and jaundiced (common bile duct ligation). At 7, 10, 14, and 21days after operation, E. coli labeled with both ¹²⁵I and ⁵¹Cr were injected intravenously. Using the previously validated double-labeled in vivo E. coli technique, hepatic phagocytic clearance (HPC), hepatic killing efficiency (HKE), and net hepatic killing (NHK) were measured. Common bile duct ligation resulted in a significant decrease in the HPC of E. coli 10, 14, and 21days postoperatively. Similarly, HKE was significantly decreased in jaundiced animals by postoperative day 10, but returned to baseline values by day 14. The net effect of these changes in HPC and HKE values were reflected in a significant reduction in NHK in jaundiced animals. Results of the present study suggest that obstructive jaundice impairs both phagocytosis and phagocytic killing within the liver. These findings may help to explain the susceptibility of patients with biliary tract obstruction to the morbidity and mortality of septic complications. Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (poster presentation).     

Primary common bile duct anastomosis in the rat using microsurgical techniques

In a rat model, we attempted to describe the natural healing course of the common bile duct (CBD) after primary microsurgical repair. Fifty-three rats were divided into experimental groups with CBD microsurgical anastomoses and control groups with CBD mobilization and ligation. Examination of three experimental groups at 1 week, 1 month, and 3 months showed evolving inflammation and stricture changes with eventual patent, healed ducts in 92% of animals at the end of 3 months following transection and repair. There were no histologic abnormalities in the livers. There were fibrotic ducts and hepatic stasis and cirrhosis changes in the control group with CBD ligation. This study demonstrates that microsurgical techniques can achieve successful primary biliary repair in the rat. © 1994 Wiley-Liss, Inc.     

阻塞性黄疸大鼠术前胆道内、外引流对肝细胞再生能力的影响

目的　探讨阻塞性黄疸大鼠肝叶切除术前胆道内、外引流对肝细胞再生能力的影响和机制。方法　将大鼠胆总管结扎 5d后 ,分别行胆道内、外引流 5d ,再行 70 %肝叶切除术。结果　胆道外引流组与内引流组和对照组大鼠相比 ,反映肝细胞再生能力的肝细胞核DNA含量、增殖细胞核抗原 (proliferatingcellnuclearantigen ,PCNA)指数、有丝核分裂指数 (mitoticindexMI)明显减低 (P <0 0 5 )。胆道外引流组肝细胞C met/HGF R基因表达也减低 (P <0 0 1)。结论　阻塞性黄疸大鼠肝叶切除术前胆道外引流对肝细胞再生能力有明显抑制作用 ;胆道外引流组肝细胞C met/HGF R基因表达减弱可能是该组肝细胞再生能力下降的重要因素。     

Biliary stricture due to neuroma after an innocent blunt abdominal trauma

A traumatic neuroma of the biliary tract is rarely associated with biliary obstruction. However, when it arises in the common bile duct (CBD) and is associated with obstructive jaundice, it is difficult to distinguish it from bile duct cancer. We describe a patient who developed obstructive jaundice and itching, due to CBD stricture, 8 years after innocent blunt abdominal trauma. The stricture was resected and hepatico-jejunal anastomosis was performed. Histological examination revealed a traumatic neuroma and a fibrous scar around the common bile duct. Symptoms disappeared following surgical removal of the lesion. Blunt abdominal injury may cause the late onset of a fibrous scar and traumatic neuroma in the common bile duct. To our knowledge, a traumatic neuroma of the biliary tract after blunt abdominal trauma has not been reported previously. We review the clinical picture of this relatively rare problem, along with its diagnosis, pathogenesis and treatment.     

Effect of Glutamine and Bile Acid on Hepatocyte Apoptosis after Bile Duct Ligation in the Rat

Apoptosis is an important process in a wide variety of biologic systems. Cholestasis, or impaired bile formation, occurs in a wide variety of human liver diseases. Retention and accumulation of toxic hydrophobic bile salts in hepatocytes may cause hepatocyte toxicity by inducing apoptosis. In addition, the translocation of bacteria and endotoxin, well documented in patients with obstructive jaundice, contribute to the induction of hepatocyte apoptosis. We hypothesized that oral bile acid replacement, glutamine administration, or both can attenuate or abolish hepatocyte apoptosis. Male Sprague-Dawley rats weighing 250 to 300 g were randomized to four groups (10 in each group). Group 1 underwent a sham operation and was simultaneously treated with normal saline. Group 2 underwent common bile duct (CBD) ligation and was simultaneously treated with normal saline. Group 3 underwent CBD ligation and was simultaneously treated with oral glutamine. Group 4 underwent CBD ligation and was simultaneously treated with oral bile acid replacement. After 3 days (n = 5) and 7 days (n = 5), liver tissues were harvested for histopathologic analysis and apoptosis measurements. When compared with the sham operation group, significantly increased hepatocyte apoptosis and ductular proliferation occurred after CBD ligation for either 3 or 7 days. After administration of either glutamine or bile acid, the increased hepatocyte apoptosis and ductular proliferation after CBD ligation for 3 days were significantly diminished. However, both failed to diminish the changes after CBD ligation for 7 days. Significantly increased hepatocyte apoptosis and ductular proliferation occurred after CBD ligation. The administration of either glutamine or bile acid effectively diminished the hepatocyte apoptosis and ductular proliferation after CBD ligation for 3 days, whereas both failed to show the same effect after CBD ligation for 7 days.     

Role of renal sympathetic nerve activity in renal failure associated with obstructive jaundice in the rat.

The propensity for renal failure associated with obstructive jaundice and liver disease may be related to enhanced vasoconstriction of the renal vascular bed with resultant decreases in renal blood flow. Renal sympathetic nervous activity may be a mediator of this effect. The increased renal production of prostaglandins which has been observed in previous models of bile duct ligation may serve to counterbalance the effects of such vasoconstricting influences. This study was undertaken to assess the effect of bile duct ligation on renal function and prostaglandin production in the rat. Furthermore, this study was designed to determine if renal sympathetic nerve activity contributes to the development of renal failure after bile duct ligation. Sprague-Dawley rats underwent either sham operation (n = 8), bilateral renal denervation (n = 10), bile duct ligation alone (n = 11), or bile duct ligation and bilateral renal denervation (n = 10). Renal function was assessed before and 4 days after operation. Bile duct ligation resulted in a 46% decrease in creatinine clearance (p less than 0.01), a 33% decrease in urinary sodium excretion (p less than 0.01), a twofold increase in urine flow (p less than 0.01), and twofold increases in urinary excretion of PGE2, 6-keto-PGF1 alpha, and thromboxane B2 (p less than 0.01). Renal denervation did not prevent the decreases in creatinine clearance and sodium excretion seen after bile duct ligation and had no effect on the changes in urine flow and prostaglandin excretion. These findings demonstrate that bile duct ligation in the rat results in impaired renal function, accompanied by increases in renal prostaglandin production. In addition, this study indicates that the perturbations in renal function and renal prostaglandin production induced by bile duct ligation are not mediated by renal sympathetic nerve activity.     

Endotoxemia after relief of biliary obstruction by internal and external drainage in rats

Systemic and portal endotoxemia were studied in rats with biliary obstruction and after relief of the obstruction by internal and external drainage. Endotoxemia was increased after bile duct ligation (p less than 0.001) compared with control values. The incidence of systemic and portal endotoxemia was significantly reduced after internal drainage (p less than 0.001). A significantly higher incidence of portal (86 percent) and systemic (57 percent) endotoxemia, however, was found after external drainage. The persistence of endotoxemia after external drainage, when serum bilirubin levels returned to normal units, indicates that bile flow is important in controlling endotoxemia during preoperative biliary drainage. These results suggest that the systemic endotoxemia observed after relief of obstruction by external drainage may contribute to the increased mortality, as found in previous rat studies. This observation may contribute to an understanding of why patients with preoperative external drainage of biliary obstruction have a higher incidence of septic complications.