Biliary Obstructed Research Articles

An Atypical Cause of Biliary Obstruction

The aim of this case of atypical metastatic melanoma is to highlight the need for endoscopic evaluation in any biliary obstructed patient with a diagnosis of cutaneous melanoma. A 69 year old CM with a history of HTN, CAD, and skin SCC presented with abdominal pain and N/V for two weeks. He was diagnosed with acute pancreatitis. CT scan showed an enlarged pancreatic head, enlarged hilar lymph nodes, and many subcutaneous nodules. A nodule biopsy was positive for S-100 and Melan-A indicating melanoma. He was discharged but later returned in two months with worsened abdominal pain and jaundice. His bilirubin was 20. A repeat CT showed a CBD of 14 mm. An ERCP performed showed a 3 cm ulcerated dark mass in the duodenum distal to the ampulla, a distal CBD stricture, and a one cm dark nodule in the 2nd part of the duodenum. A sphincterotomy was performed with placement of a biliary stent. Duodenal mass biopsies demonstrated metastatic melanoma. Symptom relief was achieved after the procedure but given the progression of his malignancy, the patient deceased one week later. Malignant melanoma is one of the most common cancers to metastasize to the GI tract. Post-mortem studies have identified GI metastases in 60% of disseminated melanoma patients. An autopsy study of malignant melanoma patients showed the most common sites of metastases in the GI tract were liver, small bowel, colon, stomach, and then duodenum. The extremities are the most common source for GI tract melanoma metastases. Detection of GI metastases usually varies between 21-54 months after the primary melanoma diagnosis. These metastases can be found with PET scans, CT scans, barium studies, EGD, ERCP, or colonoscopy. Stains S-100 and HMB-45 on endoscopic biopsies can help confirm the diagnosis. The prognosis of metastatic melanoma to the GI tract is poor with a median survival of 12 months and a 14% five year survival rate. Treatment options for GI melanoma metastases include surgical resection, chemotherapy, or immunotherapy. Presented here is a case of melanoma metastatic to the GI tract that is atypical in its presentation of jaundice, biliary ductal dilation, and pancreatitis due to its duodenal location. The duration of two months between the patient's initial melanoma diagnosis and detection of duodenal melanoma metastases was also unique. This case illustrates the need to endoscopically evaluate any melanoma patient who presents with abdominal symptoms or signs of biliary obstruction.Figure. 3: cm ulcerated periampullary mass.

The protective effect of Nigella sativa oil in the brain of the biliary obstructed rats

ABSTRACT: Oxidative stress is one of the important mechanisms of jaundice induced encephalopathy. The aim of this study was to examine the possible protective effect of Nigella sativa (NS) seed oil against the oxidative stress of brain tissue induced by experimental obstructive jaundice in rats. BiliarY obstruction was performed in male Wistar albino rats by bile duct ligation and scission (BDL). Intragastric NS oil (1 mg/kg p.o.) or saline was administered for 28 days. At the end of the experiment, in the half of the rats the blood brain barrier (BBB) permeability was evaluated by Evans blue (EB) extravasation. Other rats were decapitated and brain tissue samples were obtained for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) and Na+,K+-ATPase activities. ChronIC biliary obstruction caused a significant increase in the BBB permeability which was verified by EB extravasation while this effect was attenuated by NS oil treatment. On the other hand, BDL-induced decrease in brain GSH level and Na+,K+-ATPase activity were elevated back to control level in NS oil-treated BDL group. Increase in tissue MDA level, and MPO activity due to BDL were also attenuated by NS oil treatment. Our results suggest that NS oil treatment protects the brain from oxidative damage following bile duct ligation in rats. This effect possibly involves the inhibition of neutrophil infiltration and lipid peroxidation and the restoration of antioxidant status in the tissue. Accordingly, supplementing cirrhotic patients with adjuvant therapy of NS oil may have some benefit against hepatic encephalopathy. KEYWORDS: Nigella, black cumin, bile duct, brain, edema

Restoration of hepatocytes function following decompression therapy in extrahepatic biliary obstructed patients: Metabolite profiling of bile by NMR

Prolonged biliary obstruction and infection cause retention of biliary constituents in liver followed by hepatocyte dysfunction. Decompression therapy is important for both management and prognostic reasons and restores hepatocyte function. Quantitative metabolite profiling of bile using NMR spectroscopy at the time of obstruction and serially following decompression therapy using percutaneous transhepatic biliary drainage (PTBD) from nineteen patients with extrahepatic malignant biliary obstruction are presented. Based on detailed history, clinical condition, total leucocyte counts (TLC) and microbiological cultures of bile, patients were classified in two groups depending upon absence or presence of cholangitis. Statistical analysis was performed for comparison within each group using Wilcoxan sign square rank test. TLC and liver function tests indicated a trend towards recovery following decompression by one week. While on day 0 biliary constituents were undetectable in both the groups of patients, they increased significantly following one week of drainage with better recovery in patients with cholangitis compared to without. Free amino acids’ signals were detected in all specimens starting from day 1 after decompression. This indicates disruption of blood–bile barrier during cholestasis and slow restoration of tight junction of hepatocytes following decompression leading to the appearance of biliary constituents in bile. Decompression therapy tends to restore biliary constituents with a prompt recovery in patients with cholangitis further supports such therapy for clinical management and outcome. To our knowledge this is the first report on the detection of amino acids in bile taken from common bile duct though they have been reported in hepatic bile.

UP-REGULATED THROMBOXANE PRODUCTION IN THE RAT LIVER WITH BILIARY OBSTRUCTION DOES NOT CONTRIBUTE TO PROMOTE HEPATIC INJURY

This study sought to determine whether in vivo inhibition of thromboxane A2 (TXA2) action contribute to attenuate hepatic damage after bile duct ligation (BDL). Male Wistar rats were assigned to sham operation or BDL. At the time of operation, infusion pump with saline, ozagrel natrium (TXA2 synthase inhibitor), or SQ29548 (TXA2 receptor antagonists) was implanted in the abdominal cavity. Plasma alanine aminotransferase, aspartate aminotransferase, hyaluronic acid, and total bilirubin levels were measured at 4 days after the operation. The levels of plasma TXB2, a stable metabolite of TXA2, were significantly increased after BDL. Gene expression of TXA2 synthase was also significantly upregulated in the liver. Nonetheless, either an inhibition of TXA2 synthesis by ozagrel natrium or a blockade of TXA2 receptor by SQ29548 has no effect in every measured parameter related to hepatic function. These results indicated that despite a highly increased production in the liver, TXA2 is not directly related to the hepatic injury in BDL rats.

Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy

To study the effects of obstructive jaundice on liver regeneration after partial hepatectomy. Hepatocyte growth factor (HGF), its receptor, c-Met, vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1) mRNA expression in both liver tissue and isolated liver cells were investigated after biliary obstruction (BO) by quantitative reverse-transcription polymerase chain reaction (RT-PCR) using a LightCycler. Immunohistochemical staining for desmin and alpha-smooth muscle actin (alpha-SMA) was also studied. Regenerating liver weight and proliferating cell nuclear antigen (PCNA) labeling index, and growth factor expression were then evaluated after 70% hepatectomy with concomitant internal biliary drainage in BO rats or sham-operated rats. Hepatic TGF-beta1 mRNA levels increased significantly 14 days after BO, and further increased with duration of cholestasis. Meanwhile, HGF and VEGF tended to increase, but was not significant. In cell isolates, TGF-beta1 mRNA was found mainly in the hepatic stellate cell (HSC) fraction. Immunohistochemical studies revealed an increased number of HSCs (desmin-positive cells) and activated HSCs (alpha-SMA-positive cells) in portal areas after BO. In a hepatectomy model, liver regeneration was delayed in BO rats, as compared to sham-operated rats. TGF-beta1 mRNA was significantly up-regulated up to 48 h after hepatectomy, and the earlier HGF mRNA peak was lost in BO rats. BO induces HSCs proliferation and activation, leading to up-regulation of TGF-beta1 mRNA and suppression of HGF mRNA in livers. These altered expression patterns may be strongly involved in delayed liver regeneration after hepatectomy with obstructive jaundice.

Protective effect of polyunsaturated phosphatidylcholine on liver damage induced by biliary obstruction in rats

Background/purpose: Persistent inflammatory response secondary to congenital or acquired biliary choleastasis plays an important role in the pathophysiology of hepatic tissue damage. The polyunsaturated fatty acids (PUFA) have been shown to suppress the inflammatory reactions in vivo and in vitro. PUFA has been shown also to protect againts various types of experimental liver damage in animal models and isolated hepatocytes. Therefore, the aim of this study was to investigate the protective effect of PUFA administration on liver damage using the rat chronic biliary obstruction model. Methods: Swiss albino rats of either sex were divided into 4 groups as follows: control group (group 1, 10 rats); rats with sham operation and treated with saline group 2, 10 rats); rats with biliary obstruction (group 3, 15 rats); and polyunsaturated phophatidylcholine (PPC)-treated rats with biliary obstruction (Group 4, 15 rats). Biliary obstruction was induced by double ligation and division of the common bile duct. PUFA treatment was started 2 weeks later from biliary obstruction in doses of 50 mg/d per rat and continued for 2 weeks. All animals were killed after 4 weeks of common bile duct ligation or sham operation. Liver damage and cholestasis were determined by biochemical and histologic examinations. Results: The data showed a decrease in plasma bilirubin level (both conjugated and unconjugated) and liver enzyme levels (AST, ALT, AP, GGT, 5′-NT) in group 4, when compared with group 3 ( P < .05). Tissue levels of malondialdehyde (MDA) in group 4 was 20.00 ± 2.93 compared with that in group 3, 27.12 ± 2.96 ( P < .05). Administration of PUFA to the biliary obstructed rats resulted in inhibition of collagen accumulation ( P < .05) and ductal proliferation ( P < .05). Conclusions: PUFA reduced liver damage, ductular proliferation, and fibrosis in biliary obstructed rats. These effects suggest that it might be a useful agent to preserve liver function in patients with biliary obstruction such as biliary atresia.

Hepatic oxidative alterations in patients with extra-hepatic cholestasis. Effect of surgical drainage

Background/Aims: The mechanisms of liver injury in conditions of biliary obstruction are poorly understood. Hepatic oxidative injury has been observed in experimental models of cholestasis. Little is known in humans. This study aimed to gain more insights into the hepatic redox status in human cholestasis. Methods: Liver concentrations of total glutathione, protein sulfhydryls and malondialdehyde (end-product of lipid peroxidation) were measured in hepatic specimens of 12 patients with obstructive jaundice before and after the application of an external biliary drainage and in six control subjects. Results: Compared to control subjects, biliary obstructed patients showed significantly ( P<0.001) lower concentrations of hepatic glutathione and protein sulfhydryls, and higher ( P<0.001) levels of malondialdehyde, in the presence of comparable protein concentrations. Two-weeks after the application of external biliary drainage, cholestatic indices were significantly improved and the observed changes in glutathione, protein sulfhydryls and malondialdehyde levels, significantly decreased. Conclusions: This study shows that cholestasis is associated with a decreased protein and non-protein sulfhydryl content in the liver and with an increased lipid peroxidation. These alterations reversed almost completely after biliary drainage, indicating the cholestasis itself as the determining factor for the redox status impairment observed in the liver of patients with extra-hepatic biliary obstruction.

Factors influencing the inhibition of biliary glutathione efflux induced by biliary obstruction

The aim of this study was to investigate mechanisms responsible for the inhibition of biliary glutathione efflux in rats with secondary biliary cirrhosis. Rats were studied after bile duct obstruction for 28 days. The biliary secretion of reduced glutathione (GSH), oxidised glutathione (GSSG) and cysteine were completely inhibited in biliary obstructed rats. Hepatic gamma glutamyltranspeptidase (γ-GT) activity increased significantly, but following its inhibition by acivicin administration GSH, GSSG and cysteine were still absent in bile. Biliary obstruction resulted in a significant increase of the permeability of the paracellular pathway, as shown by the higher bile/plasma ratio and hepatic clearance of [ 14C]sucrose. GSH and GSSG were, however, significantly lower in the carotid artery and hepatic vein of obstructed animals and the arteriovenous difference across the liver was reduced. The concentration of GSH was significantly reduced and that of GSSG increased in the liver of obstructed rats. Biliary obstruction induced an increase in the hepatic concentration of cysteine and an inhibition of both gamma glutamylcysteine synthetase and methionine adenosyl transferase activities. Dichlorofluorescein (DCF) and the GSSG/GSH ratio and thiobarbituric acid reactive substances (TBARS) concentration, markers of reactive oxygen species production and lipid peroxidation, respectively, were significantly increased. Our data indicate that increased degradation or blood reflux of glutathione do not participate in the disruption of its secretion into bile and support the view that impairment of glutathione synthesis and oxidative stress could contribute to the decline in biliary glutathione output.

The flavonoid quercetin ameliorates liver damage in rats with biliary obstruction

Background/Aims: Our aim was to investigate whether the antioxidant quercetin might protect against liver injury in chronically biliary obstructed rats. Methods: Secondary biliary cirrhosis was induced by 28 days of bile duct obstruction. Animals received quercetin at 75, 150 and 300 μmol · kg body wt −1 · day −1 i.p. through the experimental period or at 150 μmol · kg body wt −1 · day −1 i.p. for the last 2 weeks. Results: Bile duct obstruction resulted in a decrease in the activities of antioxidant enzymes. Liver oxidised/reduced (GSSG/GSH) glutathione ratio, hepatic and mitochondrial thiobarbituric acid reactive substances (TBARS) and collagen content were significantly increased and a marked fibrosis and bile ductular proliferation was observed. Quercetin corrected the reduction in glutathione concentration and partially prevented the increase in collagen concentration, TBARS and GSSG/GSH ratio. Treatment resulted in a significant preservation of the activities of antioxidant enzymes, a less pronounced fibrosis and a marked inhibition of bile ductular proliferation. Maximal effects were reached with the intermediate quercetin dose given for 2 or 4 weeks. Conclusions: Quercetin reduces liver oxidative damage, ductular proliferation and fibrosis in biliary-obstructed rats. These effects suggest that it might be a useful agent to preserve liver function in patients with biliary obstruction.

Antioxidant enzyme status in biliary obstructed rats: effects of N-acetylcysteine

Background/Aims: N-acetylcysteine (NAC) is a modulator of thiol levels that protects against hepatotoxic agents. The aim of this study was to investigate whether NAC might improve hepatic antioxidant defenses in chronically biliary obstructed rats. Methods: Secondary biliary cirrhosis was induced by 28 days of bile-duct obstruction. Groups of control and cirrhotic animals received NAC (50 μmol · kg −1 · d −1 i.m.) through the experimental period. Results: Bile-duct obstruction resulted in decreased liver glutathione concentrations. Dichlorofluorescein (DCF) and thiobarbituric acid reactive substances (TBARS) concentrations, measured as markers of production of reactive oxygen species and lipid peroxidation, respectively, were significantly increased. Microsomal and mitochondrial membrane fluidity and the activities of catalase, cytosolic and mitochondrial superoxide dismutase (SOD), glutathione S-transferase, and cytosolic and mitochondrial Se-dependent and Se-independent glutathione peroxidase (GPx) were significantly reduced. NAC corrected the reduction in glutathione concentration and partially prevented the increases in DCF and TBARS concentrations. In addition, NAC treatment resulted in significant preservation of membrane fluidity and of the activities of catalase, mitochondrial SOD and the different forms of GPx. Conclusions: Our data indicate that NAC maintains antioxidant defenses in biliary obstructed rats. These effects of NAC suggest that it may be a useful agent to preserve liver function in patients with biliary obstruction.

Pharmacokinetics of Valproic Acid in Guinea-pigs with Biliary Abnormality

To explore whether biliary cannulation, biliary obstruction or gall bladder obstruction could alter the disposition of valproic acid, guinea-pigs were subjected to common bile duct cannulation or ligation, gall bladder-neck ligation or sham surgery as a control. They were then given an intravenous (i.v.) dose of sodium valproate (50 mg kg-1) and the pharmacokinetics of valproic acid in each group were compared. In the cannulated group, significant decreases (P less than 0.05) in the area under the elimination curve (AUC), the volume of distribution at steady-state (Vdss) and the mean residence time (MRT) were observed. Significant increases (P less than 0.05) in the elimination rate constant (kz) and total clearance (CLtot) of valproic acid were noted. In the biliary obstructed guinea-pigs, the Vdss was significantly decreased (P less than 0.05). In the gall bladder obstructed guinea-pigs, there was a secondary peak of valproate plasma concentration, and the kz was significantly decreased. The biliary excretion of unchanged and conjugated valproic acid was 2.0 +/- 0.7 (s.e.m.) and 19.7 +/- 3.6 (s.e.m.)% of dose, respectively, and was almost completely reabsorbed in the enterohepatic recycling. Urinary excretion of unchanged and conjugated valproic acid, as well as non-conjugate metabolic clearance of valproic acid, were not significantly different among the four groups. The results suggest that the pharmacokinetics of valproic acid in guinea-pigs are particularly sensitive to interruption of the enterohepatic cycle. Biliary obstruction may elevate plasma concentrations owing to the decreased Vdss of valproic acid. Gall bladder obstruction may cause fluctuation of valproate plasma concentrations. The data indicate that the apparent total clearance of valproic acid is significantly less than the intrinsic clearance owing to enterohepatic recycling.

Similarities and Differences Between Models of Extrahepatic Biliary Obstruction and Complete Biliary Retention without Obstruction in the Rat

Biliary obstruction in the rat causes known biochemical and morphological abnormalities. These abnormalities might be caused simply by retention of biliary constituents or might require other factors such as high biliary pressure, interruption of the normal flux of fluid, ions, and other biliary constituents through the hepatocyte and/or changes in intracellular concentrations, binding, and distribution of biliary constituents. We studied a choledochocaval (CC) fistula rat model characterized by complete biliary retention without bile stasis. CC fistula animals were compared with biliary obstructed rats over a 46-hr period. Bile flow and bile acid excretion rate reached high levels by hour 5 and remained high in CC fistula rats. Urinary bile acid excretion, shrinkage of the rapidly exchangeable bile acid pool, and serum bile acid and bilirubin concentrations were equivalent in the two models. Serum cholesterol concentration was higher and serum alkaline phosphatase and 5'-nucleotidase activities lower in obstructed rats. The percentage of beta-muricholate rose and the percentage of cholate decreased in bile acid from obstructed rats. This was associated with increased microsomal 6 beta-hydroxylase activity. Bile acid composition and microsomal 6 beta-hydroxylase activity changed little in CC fistula rats. Morphological examination revealed greater damage in obstructed rat livers. These data indicate that factors other than simple retention of biliary constituents contribute to the abnormalities observed in extrahepatic biliary obstruction.

The effects of biliary obstruction on the rates of uptake, synthesis and secretion of 14 C-labeled cholesterol by isolated perfused rat livers.

AbstractThe isolated perfused rat liver technique was utilized to study the effect of biliary obstruction on the rates of uptake, synthesis and secretion of14C‐labeled cholesterol in an effort to elucidate the mechanism of hypercholesterolemia in this condition. By perfusing normal and biliary obstructed livers with a medium containing14C‐labeled acetate or14C‐labeled lipoprotein cholesterol and by measuring cholesterol biosynthesis in vitro, it was possible to clarify some of the questions concerning these aspects of lipid metabolism. The results of these studies revealed that the uptake of cholesterol was not altered in biliary obstruction. Instead the hypercholesterolemia of biliary obstruction arises from an increased rate of secretion of cholesterol from liver, which is accompanied by an increased rate of hepatic cholesterolgenesis. Evidence is also presented to suggest that a substance is present in biliary obstructed blood which is capable of initiating increased cholesterolgenesis in normal livers.