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Enhanced sensitivity of pancreatic cells to cholecystokinin octapeptide in obstructive jaundice.

Exocrine function of the pancreas in obstructive jaundice was examined using dogs. Jaundice induced by choledochal ligation over 3 weeks showed pancreatic hypersecretion in response to cholecystokinin octapeptide (CCK-8) stimulation. To clarify the mechanism of pancreatic hypersecretion in obstructive jaundice, three experiments were undertaken. In a perfusion experiment performed on isolated pancreas, hypersecretion in obstructive jaundice was observed in response to CCK-8 stimulation. An incubation experiment showed an increase in secretion in response to CCK-8 stimulation in a dose-dependent manner, producing a greater increase in dogs with obstructive jaundice than in controls, despite the fact that basal secretion in both groups was the same. This would suggest that at least one of the mechanisms of pancreatic hypersecretion in obstructive jaundice may be related to the degree of sensitivity of acinar cells to CCK-8. In morphological observation of acinar cells by electron microscopy, the average number of zymogen granules and total granular area per unit of cytoplasm in both groups before and after stimulation with CCK-8 were compared. There was no difference between the groups before stimulation. Following stimulation, values for the control group decreased but appeared to increase in the jaundiced pancreas. These results strongly suggest that pancreatic acinar cells in obstructive jaundice may retain their secretory potential after stimulation for 60 min, though the potential in nonjaundiced pancreatic acinar cells may decrease after stimulation.

Animals↗

[Obstructive jaundice and acute pancreatitis due to an obstruction of the afferent loop after billroth-II-resection].

An obstruction of the afferent loop after Billroth-II-resection is an extremely rare late complication of this procedure. We report on a 76-year-old female patient with a history of Billroth-II-resection 11 years ago who was admitted due to acute pancreatitis and obstructive jaundice. Abdominal sonography lead to the suspicion of a dilated afferent loop, which could be proven by means of magnetic resonance imaging. A tumorous lesion as cause of the obstructive jaundice was not detectable. Intraoperatively a volvulus of the small intestine and strangling adhesions near the Braun's anastomosis were seen, causing the obstruction of the afferent loop. Following reposition of the small intestine and adhesiolysis the patient gained a quick relief of symptoms and the jaundice disappeared completely.

Acute Disease↗

Effects of cimetidine on IL-2 and T suppressor cell function in rats with obstructive jaundice.

Susceptibility to infection in patients with obstructive jaundice is much more higher than non-jaundiced patients. The reasons for this are not completely understood. It is postulated that this may have some relation to changes of patients' immune function. This article reported the changes of splenocyte IL-2 production and T Suppressor cell activity in rats with obstructive jaundice. Meanwhile, we also investigated effects of cimetidine on immune function in rats with bile duct ligation. The results show that IL-2 production in obstructive jaundiced rats significantly decreased and T suppressor cell activity markably increased. Cimetidine could remarkably enhance IL-2 production and suppress T Suppressor cell activity. Abnormality of immune function may be one reason for high susceptibility to infection in patients with obstructive jaundice in perioperative period. Cimetidine, which could clearly improve immune function in rats with obstructive jaundice, might be a valuable agent for strengthening the capacity of fighting infection in patients with obstructive jaundice.

Adjuvants, Immunologic↗

[Endosonography in malignant extrahepatic obstructive jaundice].

34 patients with obstructive jaundice were investigated consecutively by transcutaneous ultrasonography, endoscopic sonography and endoscopic retrograde cholangio-pancreatography (ERCP). In 20 cases obstruction was due to a tumor, whose location and extent could be visualized by endosonography and ERCP in all cases. By transcutaneous ultrasonography this was possible in only 14 (70%) and 17 (85%) cases respectively. In seven of eight cases the tumor size, in four of five cases metastatic involvement of lymph nodes and in all cases infiltration into neighboring organs or vessels were correctly predicted by endosonography. Both other methods failed in this regard. We therefore conclude that the diagnostic information obtained by endosonography in patients with obstructive jaundice due to malignancy is superior to conventional sonography and ERCP.

Adult↗

Increased plasma levels of atrial natriuretic peptide and endocrine markers of volume depletion in patients with obstructive jaundice.

BACKGROUND: Hypovolaemia may cause renal dysfunction in obstructive jaundice. This study investigated whether, in patients with obstructive jaundice: (1) atrial natriuretic peptide (ANP) is increased; (2) fluid-regulating hormones are altered; and (3) biliary drainage improves fluid homoeostasis. METHODS: Forty-three patients with obstructive jaundice were investigated. A renal profile was obtained and levels of ANP, renin, aldosterone and vasopressin were determined. In a subset of 18 patients, studies were repeated 3 days after endoscopic biliary drainage and changes in extracellular volume were measured. RESULTS: Creatinine clearance was impaired in ten of 30 patients. Patients with obstructive jaundice had higher mean levels of ANP (118 versus 40 pg/ml, P = 0.0001) and aldosterone (156 versus 43 pg/ml, P = 0.0001) than matched controls. Increased renin levels were observed in ten of the 43 patients and were associated with impaired creatinine clearance. After biliary drainage ANP concentration decreased (110 versus 67 pg/ml, P = 0.004) as well as aldosterone level (182 versus 85 pg/ml, P = 0.0002) and the mean extracellular volume increased (20.5 versus 23.1 per cent of body-weight, P = 0.001). CONCLUSION: Plasma ANP concentration is increased in obstructive jaundice. Endocrine markers of hypovolaemia are activated in obstructive jaundice. After biliary drainage there is an improvement of endocrine and fluid derangements.

Aged↗

Effect of oral glutamine administration on bacterial tanslocation, endotoxemia, liver and ileal morphology, and apoptosis in rats with obstructive jaundice.

Postoperative complications in patients with obstructive jaundice remain increased when associated with endotoxemia and the inflammatory response due to gut barrier failure. Administration of glutamine has been proposed to maintain the integrity of the gut mucosa and thus reduce bacterial translocation (BT), but the effects of this pretreatment on apoptosis and histologic morphology of various organs affected by BT in obstructive jaundice have not been studied. We therefore studied the effects of oral glutamine supplementation on endotoxemia, BT, liver and terminal ileal morphology, and apoptosis in an experimental model of obstructive jaundice. A total of 60 male Wistar rats were randomly divided into four groups of 15 each: I, controls; II, sham-operated; III, bile duct ligation (BDL); IV, BDL + glutamine (4.5 g/kg/day in drinking water). Ileal samples for histology, DNA and protein content, liver biopsies, mesenteric lymph nodes (MLNs) for culture, and portal and systemic blood samples for endotoxin measurements were obtained 10 days later. Compared to the controls, a significant increase in contaminated MLN and liver samples and increased endotoxemia were noted in group III (p < 0.01) but were significantly reduced in group IV (p < 0.05). Group IV also had a significantly higher number of mitoses per crypt (M/c) (p < 0.05), less apoptotic body counts (ABCs) (p < 0.05), and a higher DNA content than did group III (p < 0.05). Liver biopsies from group III displayed typical changes of large duct obstruction that significantly improved after glutamine treatment, with decreased ductular proliferation. We concluded that supplementation of oral glutamine in the presence of obstructive jaundice ameliorates BT, endotoxemia, and apoptosis and improves the ileal and liver histology.

Administration, Oral↗

Diagnosis of obstructive jaundice.

The diagnosis of obstructive jaundice remains difficult yet vital, since operative decompression may relieve extrahepatic blockage, but operation can only harm patients with intrahepatic block or parenchymal cell inflammation or necrosis. Three new diagnostic methods (liver scanning, angiography, and transjugular transhepatic cholangiography) are reviewed, as is bilirubin metabolism, so important in the diagnosis of jaundice. Three clinical problems are discussed: extrahepatic obstruction due to cancer of the pancreas, biliary atresia causing jaundice in the newborn, and the diffuse ductal obstruction known as sclerosing cholangitis.An accurate diagnosis can usually be made with standard diagnostic techniques, such as history, physical examination and biochemical tests, and, when appropriate, gastrointestinal x-ray studies, cholecystography and cholangiography, liver biopsy, observation of the patient's course, and the three new radiological approaches mentioned above. Extrahepatic obstructive jaundice is an indication for surgical treatment, except perhaps in cases of sclerosing cholangitis.

Adult↗

Hepatic tumor necrosis factor-alpha production and distant organ dysfunction in a murine model of obstructive jaundice.

BACKGROUND: Multisystem organ dysfunction frequently occurs following obstructive jaundice, but its etiology remains unclear. This study was undertaken to evaluate the role for endogenous tumor necrosis factor-alpha (TNF-alpha) production in the renal and pulmonary injury that accompanies obstructive jaundice. METHODS: Two hundred and twenty C57BL/6 mice underwent ligation and division of the common bile duct or a sham celiotomy. The animals were randomized to receive either placebo or 1 mg/kg BW (low dose) or 15 mg/kg BW (high dose) of a novel TNF-alpha inhibitor comprised of two extracellular domains of the p55 TNF receptor linked together with polyethylene glycol. Serum bilirubin, creatinine, and urea nitrogen were determined. TNF-alpha bioactivity in plasma and organs was determined using the WEHI 164 clone 13 cytotoxicity assay. The TNF-alpha messenger RNA was detected by reverse transcriptase-polymerase chain reaction. Neutrophil infiltration into the lungs and kidney were quantitated by the myeloperoxidase assay. RESULTS: Common bile duct ligation and division resulted in rapid and sustained increases in serum bilirubin, creatinine, and urea nitrogen, peaking 2 to 5 days later. Hepatic TNF-alpha production was detected in the liver within 8 hours following obstructive jaundice, but TNF-alpha production could not be detected in the kidney or lung at any time point. Increased neutrophil infiltration occurred in the lung following obstructive jaundice peaking 5 days after obstructive jaundice. This neutrophil infiltration into the lungs could be partially inhibited (62%, P < 0.05) by administration of the novel TNF inhibitor. In contrast, neither renal nor hepatic dysfunction were affected by TNF-alpha blockade. CONCLUSIONS: Hepatic TNF-alpha production is an integral component of the response to obstructive jaundice. A TNF-alpha-mediated inflammatory response occurs in the lungs as a result of obstructive jaundice; however, renal and hepatic dysfunction do not appear to be TNF-alpha dependent since they cannot be affected by TNF-alpha blockade.

Animals↗

Monocyte and blood interleukin-12 levels in patients with obstructive jaundice.

Patients with obstructive jaundice have an increased incidence of peri-operative complications and immune dysfunction. This study was to investigate interleukin (IL)-12 (a cellular immunity stimulant), levels in jaundiced patients. 23 jaundiced patients and 17 controls were studied. There was significantly increased monocyte IL-12 production in jaundice, as measured by an ELISA, compared with that in controls (p < 0.01 by Mann-Whitney U test). A similar increase is seen in both benign and malignant jaundice. There was no difference between plasma IL-12 levels in the two groups. It is concluded that in jaundice, monocytes have a significantly increased capacity to release IL-12. This suggests that IL-12 may play a role in the immune dysfunction in jaundiced patients.

Cholestasis↗

The serum levels of soluble interleukin-2 receptor levels in patients with obstructive jaundice.

BACKGROUND/AIMS: Increased susceptibility to infection in patients with obstructive jaundice is well recognized. Depression of reticuloendothlial system phagocytic function and suppression of cellular immunity suggested by in vivo studies have been postulated as the cause. It has been shown that increased serum soluble interleukin-2 receptor (sIL-2R) levels are the marker of immune system activation, especially T cell activation. The purpose of this study was to evaluate cellular immune system activation by measuring serum sIL-2R levels in 18 patients with obstructive jaundice (11 with choledocholithiasis, 7 with malignant obstructive jaundice), 10 patients with liver cirrhosis and 10 healthy subjects. MATERIAL AND METHODS: Serum sIL-2R levels were measured by using ELISA (Boehringer Manheim). Lymphocyte subgroups were determined by flowcytometry. Serum immungolubulins (IgG, IgA, IgM) and autoantibodies such as antinuclear antibody, rheumatoid factor, anti-thyroglobulin and anti-microsomal antibody were measured. RESULTS: The levels of serum sIL-2R were found to be 47.1-121.2 (mean 77.3, SD +/- 20.1) pmol/l in healthy subjects, 82.8-199.2 (mean 150.9 +/- 32.2) pmol/L in patients with liver cirrhosis and 32.6-172.5 (mean 121.7 +/- 40.6) pmol/L in patients with obstructive jaundice. Serum sIL-2R levels were significantly higher in patients with liver cirrhosis or obstructive jaundice than in healthy subjects (p < 0.01 and p < 0.05 respectively). There is a significant difference in levels between patients with choledocholithiasis and with malignant obstructive jaundice (p < 0.01). Serum sIL-2R levels were measured higher in patients with liver cirrhosis than those in patients with obstructive jaundice (p < 0.059). CONCLUSIONS: In patients with obstructive jaundice, and to a lesser extent in those with liver cirrhosis, in vivo activation of immune system may be considered possible.

Aged↗

A randomized clinical trial of oral ursodeoxycholic acid in obstructive jaundice.

Forty patients with obstructive jaundice (bilirubin greater than 100 mumol/l) were entered into a randomized trial of oral ursodeoxycholic acid for 48 h before surgery versus no additional therapy. Pre-operative venous and operative portal total bile salt concentrations were higher in the bile salt treated patients (P less than 0.001). Portal endotoxaemia during operation was reduced in ursodeoxycholic acid treated patients (P less than 0.05). There was no significant difference in systemic venous endotoxaemia, renal function or postoperative morbidity or mortality. This study suggests pre-operative oral bile salt therapy may be of no clinical benefit in patients with obstructive jaundice.

Administration, Oral↗

The effect of pentoxifylline on the healing of intestinal anastomosis in rats with experimental obstructive jaundice.

The aims of this study were (1) to investigate the effect of experimental obstructive jaundice on the healing of intestinal anastomosis, and (2) to investigate the effect of pentoxifylline on the healing of intestinal anastomosis in rats with obstructive jaundice. Obstructive jaundice was induced in rats by the ligation and division of the common bile duct. Four days after this operation, either pentoxifylline or isotonic saline solution was administered intraperitoneally to these jaundiced rats and controls, and then intestinal anastomosis was performed. The concentrations of serum tumor necrosis factor alpha (TNF-alpha) and serum triglyceride of jaundiced and nonjaundiced rats were measured, and the quality of healing was evaluated by measuring the bursting pressure and hydroxyproline content of the anastomoses on the fifth and tenth days of anastomotic healing. Obstructive jaundice resulted in an impaired wound healing of the intestinal anastomosis in the rats. The administration of pentoxifylline to the jaundiced rats resulted in better anastomotic wound healing. The beneficial effects of pentoxifylline on anastomotic healing in rats with obstructive jaundice was attributed to its inhibitor effect on the endotoxin-induced TNF-alpha release from macrophages and monocytes, and the stabilizing effect on the neutrophils.

Anastomosis, Surgical↗

Studies in obstructive jaundice.

Acute obstruction of the extrahepatic ducts causes gross proximal duct dilatation, and elevated levels of ornithine carbamyl transferase, bilirubin, and alkaline phosphatase. Slow progressive obstruction causes variable proximal duct dilatation and in these cases bilirubin, alkaline phosphatase, and ornithine carbamyl transferase return to normal, despite the presence of severe though incomplete obstruction of the common duct and microscopic findings of biliary cirrhosis. In the early phases, ornithine carbamyl transferase is a slightly more sensitive indicator of biliary obstruction than alkaline phosphatase or bilirubin, but the values still return to normal in the face of a persistent stricture. If a patient who has previously had common duct surgery develops recurrent episodes of fever which suggest cholangitis, it should be assumed that he has a recurrent stricture, even though a cholangiogram and liver function may be normal or only slightly altered. A delay until the liver function studies show consistently raised levels may result in severe biliary cirrhosis and decreased hepatic reserve.

Acute Disease↗

Enhanced endothelial cell injury by activated neutrophils in patients with obstructive jaundice.

BACKGROUND/AIMS: A high incidence of complications has been documented in patients with obstructive jaundice after operations. Recent reports have revealed that neutrophils are involved in the mechanism causing postoperative complications. However, there are few reports investigating the interaction between neutrophils and endothelial cells in obstructive jaundice. The aim of this study was to evaluate neutrophil-mediated endothelial cell injury in patients with obstructive jaundice. METHODS: Patients were divided into three groups: those with normal liver, obstructive jaundice, and relief of obstructive jaundice. Neutrophils were isolated from patients individually. Human umbilical vein endothelial cells and neutrophils were co-cultured after addition of phorbol myristate acetate. The release of lactate dehydrogenase and thrombomodulin was measured in the medium. RESULTS: Lactate dehydrogenase and thrombomodulin were released in the co-culture medium, and Eglin C, which is an elastase inhibitor, reduced the release of lactate dehydrogenase and thrombomodulin in a dose-dependent manner. The release of lactate dehydrogenase and thrombomodulin in the group with relief of obstructive jaundice was significantly higher than in the group with normal liver. There was no significant difference between the group with obstructive jaundice and the group with normal liver. The elastase activity in neutrophil suspension was similarly higher in the group with relief of obstructive jaundice than in the group with normal liver. CONCLUSIONS: This study suggests that neutrophils in patients with obstructive jaundice are not activated before its relief. After relief of obstructive jaundice, neutrophils are strongly primed and have the potential to cause endothelial cell injury. The neutrophil "priming" in patients with obstructive jaundice may be associated with the frequent occurrence of postoperative complications.

Adult↗

Factors predicting nutritional derangements in patients with obstructive jaundice: multivariate analysis.

Patients with obstructive jaundice (OJ) that requires surgery often have malnutrition associated with increased perioperative morbidity. This study investigated the factors influencing nutritional derangements in these patients. A series of 46 OJ patients were investigated prospectively (28 malignant tumors, 18 benign obstructions). A nutritional risk index of < 83.5 was used to define protein-calorie malnutrition. Liver function, cholecystokinin (CCK), tumor necrosis factor-alpha (TNFalpha), and endotoxin levels were determined. A multivariate analysis was performed, and an obstructive jaundice malnutrition index (OJMI) was obtained. Altogether, 22 (48%) OJ patients had malnutrition (33% with benign obstructions, 57% with malignant disease). Malnourished patients had higher serum bilirubin levels (258 +/- 120 vs. 154 +/- 62 mmol/L; p = 0.005), longer duration of jaundice (16 +/- 9 vs. 9 +/- 5 days; p = 0.03), and higher plasma levels of CCK (4.0 +/- 1.3 vs. 1.7 +/- 1.0 pmol/L; p = 0.005), alanine aminotransferase (ALT) (226 +/- 209 vs. 187 +/- 161 UI/L; p = 0.01), endotoxin (15 +/- 10 vs. 6.5 +/- 7.0 EU/L; p = 0.007), and TNFalpha (69 +/- 82 vs. 23 +/- 15 pg/ml; p = 0.008) than those without malnutrition. However, only serum bilirubin, CCK, ALT, and patient age were predictors for malnutrition by multivariate analysis. Malnutrition might be expected (95% confidence interval) in patients older than 68 years with increased bilirubin (> 290 mmol/L) and ALT (> 210 UI/L) levels that corresponded with an OJMI > 55. It was concluded that nutritional alterations in patients with obstructive jaundice were determined by the intensity of the biliary obstruction correlated with increased plasma CCK levels as well as with liver dysfunction and patient age.

Aged↗

Inflammatory response in patients with malignant obstructive jaundice.

OBJECTIVE: Surgery in patients with malignant obstructive jaundice is associated with increased risks for postoperative septic complications. The aim of this study was to investigate the inflammatory and the local cellular immune response in patients accepted for surgery because of tumours in the hepatic-pancreatic-biliary (HPB) tract. MATERIAL AND METHODS: Patients with obstructive jaundice (group HPB(+)) were compared with those without (HPB(-)). Patients undergoing surgery for benign abdominal disorders served as controls. Obstructive jaundice was present in 18 out of 33 HPB patients. Preoperatively, blood was analysed for bacteria, endotoxins and cytokines (TNF-alpha, IL-6 and IL-10). At operation, mesenteric lymph nodes (MLNs) were excised for bacterial cultures using standard microbiological techniques, and immunohistochemistry, using antibodies CD4 and CD8 (mainly staining T lymphocytes), CD68 (macrophages), and anti-caspase-3 (to determine the rate of apoptosis). RESULTS: Bacterial translocation was not demonstrated in any of the patients. Increased preoperative concentrations of endotoxins were found in group HPB(+). The number of macrophages and the rate of apoptosis in MLNs were increased in jaundiced patients, while the number of T lymphocytes was decreased. CONCLUSIONS: Malignant obstructive jaundice causes increased blood concentrations of endotoxins and cytokines, an increased number of macrophages in MLNs, a higher rate of apoptosis in MLNs, but a decreased number of T lymphocytes in MLNs. The lymphocyte depletion is probably due to the increased rate of apoptosis, and might reduce the ability of jaundiced patients to eradicate infection.

Adult↗

Magnetic resonance in obstructive jaundice.

Twelve cases of obstructive jaundice in whom ultrasound failed to demonstrate the site and/or the cause of obstruction of the biliary tract were examined with magnetic resonance imaging (MRI), correctly diagnosing the site and cause of obstruction in 10 of 12 surgically proven cases. In one case of cholangiocarcinoma, the site of obstruction was well shown on MR but a definite cause could not be ascertained. In another patient who developed intermittent jaundice following surgery for choledochal cyst, MR demonstrated a solitary stone in the common hepatic duct. Surgical confirmation could not be achieved as the patient was lost to follow up. There were 6 cases of choledocholithiasis, 3 cases of gall bladder carcinoma and one case each of pancreatic adenocarcinoma and cholangiocarcinoma. It is believed that MRI will provide obstructive jaundice and will be able to minimize the use of percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP) in view of its ability to perform multiplanar imaging in multiple sequences.

Adenoma, Bile Duct↗

Obstructive jaundice facilitates hepatic metastasis of B16F1 mouse melanoma cells: participation of increased VCAM-1 expression in the liver.

Obstructive jaundice facilitates experimental liver metastasis in the rat model, but the detailed mechanisms of this facilitation remain unclear. This study aimed to evaluate the contribution of vascular cell adhesive molecules-1 (VCAM-1) to augmented hepatic metastasis in cases of obstructive jaundice. Obstructive jaundice was induced in male C57BL/6 mice by common bile duct obstruction for 5 days using a Surgiclip. For the biliary decompression, obstructive jaundice was induced for 5 days, followed by removal of the Surgiclip. Liver specimens and blood samples were obtained from animals 5 days after biliary obstruction (OJ5) or sham operation and 2, 5, 11, 14 days after biliary decompression. The expression of VCAM-1 mRNA was increased in the livers from the OJ5 group. Western blot analysis demonstrated increased expression of VCAM-1 protein in the livers of the OJ5 group, in contrast with low VCAM-1 expression in the sham group. The expression of VCAM-1 protein was sustained at high levels at 2 days and decreased at 5 days after biliary decompression (BD5). For the induction of experimental hepatic metastasis, male C57BL/6 mice were randomized to three groups (sham, OJ5, BD5) of six animals each. B16F1 melanoma cells were introduced into the animals by an intraportal injection. Metastatic colonies in the livers were investigated 13 days after inoculation. The mean number of metastatic colonies was significantly increased in the OJ5 group (70.5+/-51.2) compared to that of the sham group (7.2+/-7.9) (p<0.05). This augmentation of hepatic metastasis was abrogated in the BD5 group (16.8+/-20.3). In conclusion, our results suggest that augmented hepatic metastasis in cases of obstructive jaundice are partly mediated through VCAM-1/VLA-4 interaction.

Animals↗