[The descending pathophysiology model of cholestatic liver disease].

Intrahepatic cholestasis is a pathological condition in which the synthesis, secretion, and excretion of bile are blocked, and thus the bile does not flow normally into the duodenum and bloodstream. According to cytological damage site, it can be divided into hepatocellular cholestasis, biliary duct cell cholestasis and mixed cell cholestasis. The two kinds of pathophysiological models [ascending or upstream (damage begins with cholangiocytes and then extends to the hepatocytes) and descending or downstream (the damage starts from the liver cells and then extends to the bile duct cells)] has distinct features in the process of disease occurrence and development. This article mainly elaborates the "descending" pathophysiological model of cholestatic liver disease (hepatocytic damage progresses to biliary duct cell), and further explores its etiology, pathogenesis and treatment methods.

Effect of probiotic supplementation on bacterial translocation in common bile duct obstruction.

OBJECTIVE: To investigate the effects of probiotics on bacterial translocation in the obstructive common bile duct with comparison to an enteral product containing arginine and glutamine. MATERIAL AND METHOD: In our study, 40 Sprague-Dawley rats each weighing 250-300 g were used. Animals in Group 1 (sham) were laparatomized and fed standard chow supplemented with physiologic saline at daily doses of 2 ml through orogastric tube for 7 days. Common bile ducts of the animals in the other groups were ligated with 3/0 silk sutures. Group 2 (control group) was fed standard chow supplemented with daily doses of 2 ml physiologic saline. Group 3 (probiotic group) was fed standard chow supplemented with a probiotic solution (Acidophilus plus) containing strains of Lactobacillus acidophilus, Bifidobacterium bifidum and Lactobacillus bulgaricus at a daily doses of 2 × 10(9) colony forming units (CFU). Group 4 (formula group) was fed only an enteral solution (Stresson Multi Fiber) containing glutamine, arginine and a medium-chain fatty acid at daily doses of 2 g/kg. At the end of the 7th day, all animals were relaparatomized, and to determine bacterial translocation, aerobic, and anaerobic cultures were obtained from the specimens of mesenteric lymph nodes, intestinal mucosa, and blood samples. Smear cultures prepared from caecum were examined to determine the number of CFU. Finally, for histological examination specimens were excised from terminal ileum, and oxidative damage was assessed in liver tissues. Afterwards all animals were killed. RESULTS: Moderately lesser degrees of bacterial translocation, and mucosal damage were seen in Groups 3, and 4 relative to Group 2 (p < 0.05). In Group 4, any difference was not seen in the number of cecal bacteria relative to baseline values, while in Group 3, significant decrease in cecal colonization was seen. Among all groups, a significant difference between levels of malondialdehyde, and glutathione was not observed. CONCLUSION: At the end of our study, we have concluded that both probiotics, and enteral diets which contain immunomodulators such as glutamine, and arginine alleviate bacterial translocation, and impairment of intestinal mucosa.

The effect of ursodeoxycholic acid on oxidative stress level and DNase activity in rat liver after bile duct ligation.

Accumulation of hydrophobic bile acids (BAs) during cholestasis plays an important role in apoptosis initiation as well as oxidative stress increase in liver cells. Ursodeoxycholic acid (UDCA) acts as a protector in BA-induced cell injury.The aim of the study was to evaluate the effect of UDCA on oxidative stress level and DNase I and II activity caused by liver injury in bile duct ligation (BDL) rats.Wistar rats were divided in four groups: group 1, control (sham-operated); group 2, sham-operated and injected with UDCA (30 mg/kg); group 3,animals with BDL; and group 4,UDCA-treatedcholestatic rats. Animals were sacrificed after 9 days. Malondialdehyde (MDA; lipid peroxidation end-product) level and protein-molecule oxidative modification (carbonyl group content) significantly increased in BDL rat liver. Catalase (CAT) activity in liver tissue was found to be decreased in BDL rats. In addition, xanthine oxidase (XO) activity, which is thought to be one of the key enzymes producing reactive oxygen species, was found to be increased in the cholestatic group. The apoptotic effect in cholestasis was probably triggered by the increased activation of DNase I and II. The protective effect of UDCA on liver tissue damage in BDL rats, in comparison to cholestatic liver, were 1) decrease of MDA levels, 2) increased CAT activity, 3) reduced XO activity, and 4) effect on terminal apoptotic reaction, shown as a decrease in DNase I and II activity.Therefore, UDCA may be useful in the preservation of liver function in cholestasis treatment.

Darbepoetin-α inhibits the perpetuation of necro-inflammation and delays the progression of cholestatic fibrosis in mice.

Biliary obstruction and cholestasis result in hepatocellular necro-inflammation and lead to the development of liver fibrosis. The objective of this study was to analyze whether the multiple tissue-protective properties of erythropoietin are salutary in an experimental model of liver fibrosis. For this purpose, C57BL/6J mice underwent common bile duct ligation (BDL) and were treated with either darbepoetin-α (10 µg/kg i.p.) or physiological saline every third day, beginning 24 h after BDL. Mice were killed at 2, 5, 14, and 28 days after BDL. Beside hematological parameters, markers of inflammation and fibrosis were assessed histomorphometrically and immunohistochemically as well as by quantitative real-time PCR. In addition, a 7-week survival study was performed. BDL provoked cholestatic hepatitis characterized by biliary infarcts with accumulation of macrophages followed by marked collagen deposition and increased expression of profibrotic gene transcripts. Darbepoetin-α treatment significantly diminished the area of focal necrosis, reduced the infiltration of macrophages, decreased levels of profibrotic genes, and lowered collagen deposition. Moreover, darbepoetin-α significantly reduced systemic anemia caused by BDL. Finally, darbepoetin-α treatment significantly prolonged the survival time after BDL. This study suggests that darbepoetin-α, which is a clinically well-established substance, might be used as an efficient therapeutic option for patients with chronic cholestatic liver disease.

High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis.

UNLABELLED: Fibroblast growth factor 19 (FGF19) is an endocrine factor produced by the small intestine in response to uptake of luminal bile salts. In the liver, FGF19 binds to FGF receptor-4, resulting in down-regulation of cytochrome P (CYP) 7A1 and reduced bile salt synthesis. Down-regulation of CYP7A1 under cholestatic conditions has been attributed to bile salt-mediated induction of the transcriptional repressor short heterodimer partner (SHP), because the interrupted enterohepatic cycle of bile salts is thought to abrogate intestinal FGF19 production and thus result in lowering of plasma FGF19 levels. Unexpectedly, we observed marked elevation of plasma FGF19 in patients with extrahepatic cholestasis caused by a pancreatic tumor (2.3 +/- 2.3 in cholestatic versus 0.40 +/- 0.25 ng/mL and 0.29 +/- 0.12 ng/mL in postcholestatic patients who received preoperative drainage by biliary stenting, P = 0.004, and noncholestatic control patients, P = 0.04, respectively). Although FGF19 messenger RNA (mRNA) is virtually absent in normal liver, FGF19 mRNA was strongly increased (31-fold to 374-fold, P < 0.001) in the liver of cholestatic patients in comparison with drained and control patients. In the absence of changes in SHP mRNA, CYP7A1 mRNA was strongly reduced (7.2-fold to 24-fold, P < 0.005) in the liver of cholestatic patients in comparison with drained and control patients, indicating an alternative regulatory pathway. Alterations in transcripts encoding hepatobiliary transporters [adenosine triphosphate-binding cassette, subfamily C, member 3 (ABCC3)/multidrug resistance protein 3 (MRP3), organic solute transporter alpha/beta (OSTalpha/beta), organic anion-transporting polypeptide (OATP1B1)] further suggest that bile salts are secreted via a nonbiliary route in patients with extrahepatic cholestasis. CONCLUSION: The liver expresses FGF19 under conditions of extrahepatic cholestasis. This is accompanied by a number of adaptations aimed at protecting the liver against bile salt toxicity. FGF19 signaling may be involved in some of these adaptations.

Divergent effects of irritants on the gastric mucosa in rats during various stages after bile duct ligation.

BACKGROUND AND AIM: Controversy exists as to whether rats after bile duct ligation (BDL) are more susceptible to gastric mucosal damage (GMD) induced by irritants. In the present study we characterize GMD after intragastric instillation of either ethanol or hydrochloric acid (HCL), 3 and 21 days after the surgical procedure. METHODS: Bile duct ligation and sham operated (SO) rats were studied. RESULTS: Three days after surgery, BDL rats exhibited a reduction in gastric mucosal nitric oxide synthase (NOS) activity but an increase in ethanol-induced GMD. Twenty-one days after surgery gastric mucosal prostaglandin (PG) E(2) generation in BDL rats was increased while NOS activity in both groups was similar. Ethanol-induced GMD in SO rats was higher. Pretreatment with NG-nitro-L-arginine methyl ester, prior to ethanol administration was associated with an increase in gastric mucosal PGE(2) generation: (147% in SO and 104% in BDL rats) and in GMD (176% in SO and 303% in BDL rats). HCL induced GMD was of similar magnitude in both groups in both time periods. CONCLUSIONS: The gastric resistance to damage by irritants in rats with BDL is not a static phenomenon. This may result from sequential changes that occur in the gastric mucosal defense mechanisms during the evolution of liver disease.

Opioid receptor antagonist promotes angiogenesis in bile duct ligated rats.

BACKGROUND AND AIM: Angiogenesis, formation of new capillaries from existing vasculature, plays a pivotal role in different pathological states such as many chronic inflammatory diseases including the chronic liver diseases. There is increasing evidence demonstrating accumulation of endogenous opioids and their role in the pathophysiology and manifestations of cholestasis, the main feature of a number of chronic progressive liver diseases. Hence, we investigated the significance of endogenous opioids in angiogenesis in an experimental model of cholestasis. METHODS: Cholestasis was induced in male Sprague-Dawley rats by bile duct ligation and resection. Naltrexone, an opioid antagonist (20 mg/kg/day) was administered to cholestatic animals for 22 +/- 1 days. The serial sections from liver tissue were stained with von Willebrand Factor antibody and micro-vessel density was assessed by calculating mean micro-vessel number in three hot spots high power microscopic fields. RESULTS: Naltrexone treatment in bile duct ligated rats led to a marked increase in the micro-vessel number (6.34 +/- 0.21 vs 5.61 +/- 0.22) (P < 0.05), which had already increased during cholestasis. CONCLUSION: In order to clarify the impacts of opioid system blockade in cirrhosis, our findings demonstrate the promoting role of opioid antagonist in angiogenesis in a rat model of cholestasis.

Biliary fibrosis in microsurgical extrahepatic cholestasis in the rat.

A new model of extrahepatic cholestasis, using a microsurgical technique, is performed as an alternative to the traditional model of the bile duct ligated-rat, in order to study the stage of fibrosis in the long-term. Male Wistar rats were divided into two groups: I (Sham-operated, n = 9) and II [Microsurgical Cholestasis (MC), n = 10]. After 4 weeks, portal pressure, types of portosystemic collateral circulation, mesenteric venous vasculopathy, hepatic function test, and liver histopathology were studied by using the Knodell index and fibrosis was determined by reticulin and Sirius red stains. The animals with MC presented portal hypertension with extrahepatic portosistemic collateral circulation, associated with mesenteric venous vasculopathy and increased plasma levels of bilirubin (6.30 +/- 1.80 vs. 0.22 +/- 0.37 mg/dL; P = 0.0001), alkaline phosphatase (293.00 +/- 82.40 vs. 126.30 +/- 33.42 U/L; P = 0.001), AST (380.00 +/- 78.50 vs. 68.33 +/- 11.74 IU/L; P = 0.0001), ALT (87.60 +/- 22.32 vs. 42.22 +/- 7.89 IU/L; P = 0.0001), and LDH (697.76 +/- 75.13 vs. 384.80 +/- 100.03 IU/L; P = 0.0001). On the contrary, plasma levels of albumin decreased (2.72 +/- 0.12 mg/dl vs. 2.99 +/- 0.10; P = 0.001). The microsurgical resection of the extrahepatic biliary tract in the rat produces an experimental model of hepatic inflammation, characterized by a high Knodell hepatic activity index (4), bile proliferation, and fibrosis.

Jaundice in the emergency department: meeting the challenges of diagnosis and treatment [digest].

There are approximately 52,000 visits a year to emergency departments for patients presenting with jaundice. While many of these patients will not have immediately life-threatening pathology, it is essential that the emergency clinician understands the pathophysiology of jaundice, as this will guide the appropriate workup to detect critical diagnoses. Patients who present with jaundice could require intravenous antibiotics, emergent surgery, and, in severe cases, organ transplantation. This issue will focus on the challenge of evaluating and treating the jaundiced patient in the ED using the best available evidence from the literature. [Points & Pearls is a digest of Emergency Medicine Practice.].

Jaundice in the emergency department: meeting the challenges of diagnosis and treatment.

There are approximately 52,000 visits a year to emergency departments for patients presenting with jaundice. While many of these patients will not have immediately life-threatening pathology, it is essential that the emergency clinician understands the pathophysiology of jaundice, as this will guide the appropriate workup to detect critical diagnoses. Patients who present with jaundice could require intravenous antibiotics, emergent surgery, and, in severe cases, organ transplantation. This issue will focus on the challenge of evaluating and treating the jaundiced patient in the ED using the best available evidence from the literature.

Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.

To establish the role of the biliary epithelium in bile formation, we studied several aspects of biliary physiology in control rats and in rats with ductular cell hyperplasia induced by a 14-d extrahepatic biliary obstruction. Under steady-state conditions, spontaneous bile flow was far greater in obstructed rats (266.6 +/- 51.9 microliters/min per kg) than in controls (85.6 +/- 10.6 microliters/min per kg), while excretion of 3-hydroxy bile acids was the same in the two groups. Infusion of 10 clinical units (CU)/kg per h secretin produced a minimal choleretic effect in controls (+3.8 +/- 1.9 microliters/min per kg) but a massive increase in bile flow in the obstructed animals (+127.8 +/- 34.9 microliters/min per kg). Secretin choleresis was associated with an increase in bicarbonate biliary concentration and with a decline in [14C]mannitol bile-to-plasma ratio, although solute biliary clearance significantly increased. Conversely, administration of taurocholate (5 mumol/min per kg) produced the same biliary effects in control rats and in rats with proliferated biliary ductules. In the obstructed animals, the biliary tree volume measured during taurocholate choleresis (67.4 +/- 15.8 microliters/g liver) was significantly greater than that determined during the increase in bile flow induced by secretin (39.5 +/- 10.4 microliters/g liver). These studies indicate that, in the rat, the proliferated bile ductules/ducts spontaneously secrete bile and are the site of secretin choleresis. Furthermore, because the proliferated cells expressed phenotypic traits of bile ductular cells, our results suggest that whereas under normal conditions the biliary ductules/ducts in the rat seem to contribute little to bile formation, secretion of water and electrolytes is a property of biliary epithelial cells.

Extrahepatic obstructive cholestasis reverses the bile salt secretory polarity of rat hepatocytes.

To elucidate the consequences of extrahepatic cholestasis on the structure and function of hepatocytes, we studied the effects of bile duct ligation on the turnover, surface distribution, and functional activity of the canalicular 100-kD bile salt transport protein (cBSTP). Basolateral (blLPM) and canalicular (cLPM) liver plasma membrane vesicles were purified to the same degree from normal and cholestatic rat livers and the membrane bound cBSTP identified and quantitated using polyclonal anti-cBSTP antibodies. Cholestasis of 50 h resulted in an increased release of cBSTP into bile, thereby decreasing its in vivo half-life from 65 to 25 h. Furthermore, a significant portion of cBSTP accumulated at the basolateral surface and in intracellular vesicles of cholestatic hepatocytes. This redistribution of cBSTP was functionally paralleled by decreased and increased electrogenic taurocholate anion transport in cLPM and blLPM vesicles, respectively. These results demonstrate that biliary obstruction causes a reversal of the bile salt secretory polarity of rat hepatocytes. The resulting increase in basolateral (sinusoidal) bile salt efflux might protect hepatocytes from too high an accumulation of toxic bile salts within the cell interior.

Yin-Chen-Hao-Tang ameliorates obstruction-induced hepatic apoptosis in rats.

The accumulation of hydrophobic bile acids in the liver is considered to play a pivotal role in the induction of apoptosis of hepatocytes during cholestasis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. Yin-Chen-Hao-Tang (YCHT) decoctions have been recognised as a hepatoprotective agent for jaundice and various types of liver diseases. We used an experimental rat model of bile-duct ligation (BDL) to test whether YCHT plays a regulatory role in the pathogenesis of hepatic apoptosis. BDL-plus-YCHT groups received 250 or 500 mg kg (-1) YCHT by gavage once daily for 27 days. YCHT significantly ameliorated the portal hypertensive state and serum TNF-alpha compared with the vehicle-treated control group. In BDL-plus-YCHT-treated rats, hepatic glutathione contents were significantly higher than than in BDL-only rats. BDL caused a prominent liver apoptosis that was supported by an increase in Bax and cytochrome c protein and increased expression of Bax and Bcl-2 messenger RNA. The normalising effect of YCHT on expression of Bax and Bcl-2 mRNA was dependent on the dose of YCHT, 500 mg kg (-1) having the greater effect on both Bax and Bcl-2 of mRNA levels. Additionally, YCHT treatment down-regulated both hepatic caspase-3 and -8 activities of BDL rats. This study demonstrates the anti-apoptotic properties of YCHT and suggests a potential application of YCHT in the clinical management of hepatic disease resulting from biliary obstruction.

Growth evaluation in infants with neonatal cholestasis.

BACKGROUND: [corrected] Chronic liver diseases in childhood often cause undernutrition and growth failure. To our knowledge, growth parameters in infants with neonatal cholestasis are not available AIM: To evaluate the nutritional status and growth pattern in infants with intrahepatic cholestasis and extrahepatic cholestasis. PATIENTS AND METHODS: One hundred forty-four patients with neonatal cholestasis were followed up at the Pediatric Gastroenterology Service of the Teaching Hospital, State University of Campinas, Campinas, SP, Brazil, in a 23-year period, from 1980 to 2003. The records of these patients were reviewed and patients were classified into two groups, according to their anatomical diagnosis: patients with intrahepatic cholestasis - group 1, and patients with extrahepatic cholestasis - group 2. Records of weight and height measurements were collected at 4 age stages of growth, in the first year of life: 1) from the time of the first medical visit to the age of 4 months (T1); 2) from the 5th to the 7th month (T2); 3) from the 8th to the 10th month (T3); and 4) from the 11th to the 13th month (T4). The weight-by-age and height-by-age Z-scores were calculated for each patient at each stage. In order for the patient to be included in the study it was necessary to have the weight and/or height measurements at the 4 stages. Analyses of variance and Tukey's tests were used for statistical analysis. Repeated measurement analyses of variance of the weight-by-age Z-score were performed in a 60-patient sample, including 29 patients from group 1 and 31 patients from group 2. The height-by-age data of 33 patients were recorded, 15 from group 1 and 18 from group 2 RESULTS: The mean weight-by-age Z-scores of group 1 patients at the 4 age stages were: T1=-1.54; T2=-1.40; T3=-0.94; T4=-0.78. There was a significant difference between T2 X T3 and T1 X T4. The weight-by-age Z-scores for group 2 patients were :T1=-1.04; T2=-1.67; T3=-1.93 and T4=-1.77, with a significant difference between T1 X T2 and T1 X T4. The mean weight-by-age Z-scores also showed a significant difference between group 1 and group 2 at stages T3 and T4. The mean height-by-age Z-scores at the four stages in group 1 were: T1=-1.27; T2=-1.16; T3=-0.92 and T4=-0.22, with a significant difference between T3XT4 and T1XT4. The scores for group 2 patients were: T1=-0.93; T2=-1.89; T3=-2.26 and T4=-2.03, with a significant difference between T1XT2 and T1XT4. The mean height-by-age Z-scores also showed a significant difference between group 1 and group 2 at T3 and T4 CONCLUSION: The weight and height differences between the groups became significant from the 3rd measurement onward, with the most substantial deficit found in the extrahepatic group. In this group, there is evidence that the onset of weight and height deficit occurs between the first and second evaluation stages.

Dendritic Cells Regulate Treg-Th17 Axis in Obstructive Phase of Bile Duct Injury in Murine Biliary Atresia.

Several cell types are considered to be effector cells in bile duct injury in rhesus rotavirus (RRV)-induced experimental biliary atresia (BA). Here, we identified an increased T helper 17 (Th17) cell population in a BA mode. By depleting the Th17 cells, the BA symptoms (onset of jaundice, acholic stools and retarded growth) were attenuated and the survival rate was improved. Furthermore, we found that in mice with BA, the percentage of CD4+CD25highFoxp3+ T regulatory (Treg) cells decreased along with the increased percentage of Th17 cells. However, the absolute numbers of Treg and Th17 cells were both increased in liver of RRV-injected mice compared to saline-injected mice. The proportion of Th17 cells at 7 days post-infection was decreased if Treg cells isolated from normal adult mice, but not Treg cells from the livers of mice with BA, were intraperitoneally transferred on day 5 of life. In vitro experiments also showed that Treg cells from mice with BA had a diminished suppressive effect on Th17 cell generation. To determine the mechanisms, we investigated the production of cytokines in the liver. The level of IL-6, which has been shown to be abundantly secreted by activated dendritic cells (DCs), was remarkably elevated. Importantly, in a Treg/Th17 cell suppression assay, IL-6 was demonstrated to paralyze the Treg cells' suppressive effect on Th17 cells and eventually the unrestrained increase of Th17 cells contributed to bile duct injury. In conclusion, the DC-regulated Treg-Th17 axis, probably in conjunction with other effector T cells, aggravates progressive inflammatory injury at the time of ductal obstruction.

Pharmacokinetics of phenazone (antipyrine) in rabbits with experimental common bile duct obstruction.

1. An altered functional state of liver due to experimental cholestasis could result in a change in the biotransformation of drugs. The aim of this study was to evaluate an influence of obstructive cholestasis on the pharmacokinetics of phenazone (antipyrine). 2. The investigation was carried out on male rabbits, randomly allocated into two groups: shamoperated and animals with biliary ducts ligation. Phenazone was administered intragastrically as a probe of drug metabolism. 3. Measurements, i.e. laboratory and pharmacodynamic tests, as well as pharmacokinetic assays, were performed before the operation as well as 10-12 days after the bile duct ligation. At the end of the study livers were examined macro- and microscopically and biochemical analysis of the liver microsomes was performed. 4. The measured pharmacokinetic parameters suggested an impaired biotransformation of phenazone in animals with obstructive cholestasis, leading to a slower drug elimination.

Mechanisms of cholestasis.

From the multiple mechanisms of cholestasis presented in this article, a unifying hypothesis may be deduced by parsimony. The disturbance of the flow of bile must inevitably lead to the intracellular retention of biliary constituents. Alternatively, the lack of specific components of bile unmasks the toxic potential of other components, as in the case of experimental mdr2 deficiency. In the sequence of events that leads to liver injury, the cytotoxic action of bile salts is pivotal to all forms of cholestasis. The inhibition of the bsep by drugs, sex steroids, or monohydroxy bile salts is an example of direct toxicity to the key mediator in canalicular bile salt excretion. In other syndromes, the dysfunction of distinct hepatocellular transport systems is the primary pathogenetic defect leading to cholestasis. Such dysfunctions include the genetic defects in PFIC and the direct inhibition of gene transcription by cytokines. Perturbations in the short-term regulation of transport protein function are exemplified by the cholestasis of endotoxinemia. The effect of bile salts on signal transduction, gene transcription, and transport processes in hepatocytes and cholangiocytes has become the focus of intense research in recent years. The central role of bile salts in the pathogenesis of cholestasis has, ironically, become all the more evident from the improvement of many cholestatic syndromes with oral bile salt therapy.

Biliary obstruction in hematopoietic cell transplant recipients: an uncommon diagnosis with specific causes.

Jaundice is a common problem in marrow transplant recipients. The incidence of bile duct obstruction in this setting is unknown. The purpose of this study was to determine the incidence of biliary obstruction, the causes, and outcomes following marrow transplant. Consecutive cases were reviewed at two major transplant centers in the United States from 1969 to 1996 at the Fred Hutchinson Cancer Research Center and 1989 to 1996 at the City of Hope National Medical Center. Nine cases of biliary obstruction were identified as a cause of jaundice in 7412 marrow transplant recipients, an incidence of 0.12%. The presentation was bimodal, with seven cases occurring prior to day 100 and two occurring 2 to 4 years after transplantation. The age distribution was 15 to 50 years and all patients had received allogeneic transplants. The causes of obstruction included gallbladder sludge (n=1), a duodenal hematoma (n=1), choledocholithiasis with biliary pancreatitis (n=1), bile duct infection (n=2), recurrent malignancy (n=1), choledocholithiasis associated with a benign stricture (n=1), Epstein-Barr virus-related lymphoproliferative disorder (n=1), and a benign stricture of unknown etiology (n=1). Biliary obstruction is a rare cause of jaundice in the post-transplant period. The presentation was similar to that of other post-transplant hepatobiliary problems, but with disparate causes.

Anatomic correlates of bacterial cholangiovenous reflux.

The purpose of these studies was to define the pathways by which bacteria pass from bile duct to bloodstream during acute bacterial cholangitis in the rat. The respective roles of biliary obstruction and intrabiliary pressure during the reflux of biliary bacteria were defined by the infusion of bacteria via the bile duct into rats with or without prior bile duct obstruction. As determined by quantitative blood culture analysis, bacterial reflux from bile to blood was enhanced by increased intrabiliary pressure regardless of presence or absence of biliary obstruction. Light microscopic examination of rat liver 48 hours after bile duct obstruction revealed bile ductular proliferation and bile canalicular dilatation. Light microscopic autoradiographs showed aggregates of tritiated thymidine-labeled Escherichia coli outside of interlobular bile ducts in the portal tracts. Transmission electron microscopic examination of rat liver perfused with a bacterial suspension via the common bile duct showed disruption of liver cells and formation of intracellular vacuoles. Bacteria appeared to enter the sinusoidal spaces via these intracellular vacuoles. We conclude that during retrograde biliary infusion (1) increased intrabiliary pressure is the main determinant of increased bacterial reflux into blood; (2) bacteria enter the bloodstream by predominantly intracellular pathways; and (3) prior biliary obstruction is not a significant factor in bacterial reflux from bile to bloodstream.