Effects of S-adenosyl-L-methionine on liver damage in experimental obstructive jaundice

S-adenosyl-l-methionine (SAMe) is a naturally occurring molecule distributed throughout the body tissues, including the liver. It acts as a methyl group donor and as an enzyme activator in a number of biochemical reactions. Methionine is metabolized in the liver, where it is converted to SAMe by SAMe-synthetase. In patients with liver diseases, these pathways are impaired because of the decreased contents of glutathione, the major abnormality being a reduction in SAMe-synthetase activity. Exogenous SAMe may overcome the results of impaired SAMe-synthetase activities. We conducted this study to evaluate the effect of SAMe administration on liver damage induced by biliary obstruction. Rats with common bile duct ligation exhibited abnormal liver functions, increased lipid peroxide levels, and decreased reduced glutathione contents when compared with the shammed-controls, which indicated that there was oxidative stress in rats with obstructive jaundice; however, SAMe application improved these injuries. There were significant alterations of the levels of amino acid profiles in animals with obstructive jaundice. The ratio between branch chain and aromatic amino acid was depressed, which indicated that the condition of liver was worsening, but SAMe administration improved these alterations significantly. In conclusion, SAMe administration alleviated the liver damage, indicating an important hepatoprotective effect of this methyl donor.     

Effect of oophorectomy and exogenous estrogen replacement on liver injury in experimental obstructive jaundice

AIM： To investigate the role of estrogen on liver injury in an experimental obstructive jaundice model.
METHODS： Three groups of female rats were constituted; group 1 was oophorectomized and given E2 （n = 14）, group 2 was oophorectomized and given placebo （n = 14）, and group 3 was sham operated （n = 14）. Fourteen days following constitution of bile duct ligation, all groups were compared in terms of serum tests, histopathologic parameters, and tissue levels of IFN-γ and IL-6.
RESULTS： The parameters representing both the injury and/or the reactive response and healing were more pronounced in groups 1 and 2 （χ^2= 17.2, χ^2= 10.20; χ^2= 12.4, P 〈 0.05）. In the sham operated or E2 administered groups significantly lower tissue levels of IFN-γ and higher IL-6 levels were found. In contrast, high IFN-γ and low IL-6 tissue levels were found in the oophorectomized and placebo group （P 〈 0.001）. Kupffer cell alterations were observed to be more pronounced in the groups 1 and 3 （χ^2= 6.13, P 〈 0.05）.
CONCLUSION： Our study indicates that E2 impaired liver functions, accelerated both the liver damage and healing. In the conditions of bile duct obstruction, estrogen significantly changed the cytokine milieu in the liver.     

Partially reversible renal tubular damage in patients with obstructive jaundice

Decreased serum uric acid levels resulting from renal urate wasting have been occasionally encountered in jaundiced patients. However, in these cases, there are no data concerning the underlying renal tubular defects. In the present study, we investigated the renal tubular function in 35 patients with obstructive jaundice of various severity and causes (11 with lithiasis, 17 with carcinoma, and 7 with intrahepatic cholestasis). A detailed study of the renal tubular function was performed. Beyond the conventional methods, (1)H-NMR spectroscopy of urine was used to evaluate noninvasively renal damage by the characteristic perturbation in the excretion pattern of low-molecular weight endogenous metabolites. On admission, patients with obstructive jaundice had significantly lower serum uric acid and phosphate levels and higher bile acid concentrations compared with 40 age- and sex-matched controls. Serum uric acid levels presented a negative correlation with the total and direct bilirubin as well as the fractional excretion of uric acid. Furthermore, a great number of the patients studied developed one or more proximal tubular dysfunction manifestations beyond uricosuria, such as renal glucosuria, phosphaturia, and increased excretion of alpha(1)-microglobulin. (1)H-NMR spectroscopy of the urine showed decreased levels of citrate and hippurate and increased levels of 3-hydroxybutyrate and acetate. In 12 patients partial or complete remission of jaundice was followed by an improvement of the proximal renal tubular damage. In conclusion, obstructive jaundice can cause a partially reversible generalized proximal tubular dysfunction.     

Relation between bile acids and myocardial damage in obstructive jaundice

AIM: To investigate the morphologic changes of the myocardium and its relationship to serum bile acids in obstructive jaundice.METHODS: Part 1: 35 rats were randomly assigned to three groups: Group I (BDL1, n = 11), the common bile duct (CBD) was ligated and severed and mice were then sacrificed after one week. Group I (BDL2, n = 11), the CBD was ligated and severed and mice were then killed after two weeks. Group I (SO, n = 13), the CBD was isolated. Hearts were collected for morphologic studies and blood was taken to determine the total serum bile acids (TAB). Part 2: 13 rats received gastric intubation of 10% 4 mL/kg sodium cholate. Their serum TBA and the heart’s morphologic changes were then examined.RESULTS: One to two weeks after the CBD was ligated and severed, damage was evident in the mitochondria within the myocardium and the serum TBA was significantly increased. When rats were administered sodium cholate to make their peak blood concentration mimic the average blood concentration in BDL2, a similar degree of myocardial damage was observed.CONCLUSION: An increase in endogenous bile acids is one causative factor of myocardial damage in obstructive jaundice.     

Peroxisome proliferators-activated alpha agonist treatment ameliorates hepatic damage in rats with obstructive jaundice: an experimental study

Background  

Peroxisome proliferators-activated receptor alpha (PPARα) activation modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of short-term administration of fenofibrate, a PPARα agonist, on proinflammatory cytokines, apoptosis, and hepatocellular damage in cholestasis.     

The role of insulin and glucagon in experimental obstructive jaundice.

BACKGROUND/AIMS: The oxidative phosphorylation of liver mitochondria is regulated by the amount of portal insulin available to the hepatocytes. Thus, hepatic energy is mediated by the values of blood sugar and insulin. Insulin and glucagon are the main fuel homeostats in the liver. This study was performed to investigate the concept of energy mediated by glucose, during the process of obstructive jaundice and its recovery. METHODOLOGY: Experimental Wistar rats were studied, with bile duct tied for 4, 7 and 14 days respectively. The serum concentration and relative tissue concentration of insulin and glucagon were measured. And the common bile duct was tied for 4, 7 and 14 days, then relieved by time sequences for 4, 7 and 14 days. Serum concentration and relative tissue concentration of insulin and glucagon were also measured. RESULTS: When the common bile duct was tied for 4, 7, and 14 days respectively, the serum concentration and relative tissue concentration of insulin declined (p < 0.05) and glucagon concentration was elevated (p < 0.05). When the common bile duct was tied for 4, 7 and 14 days, then relieved by time sequences for 4, 7 and 14 days, the concentrations of insulin in both groups appeared to decline at first (p < 0.05) and then progressively increase (p < 0.05). The concentrations of glucagon exhibit the reverse behavior. Both serum and tissue concentration are elevated at first (p < 0.05), then progressively decline (p < 0.05). CONCLUSIONS: These studies indicated that, during obstructive jaundice, more fuel is demanded to make up for the energy deficiency. In spite of surgical or non-surgical relief of obstructive jaundice, the energy reserve is still not sufficiently recovered. The recovery of the hepatic energy reserve takes longer than we expected.     

Short and long-term effects of bacterial translocation due to obstructive jaundice on liver damage

BACKGROUND/AIMS: The present study was conducted to determine if obstructive jaundice promotes bacterial translocation and to evaluate the changes in hepatic histopathology in patients with benign biliary obstruction. METHODOLOGY: Between January 1996 and January 1998, 19 patients treated for benign biliary obstruction were studied. Fourteen patients with symptomatic cholelithiasis were taken as the control group. Patient characteristics, preoperative and post-operative laboratory tests with an interval of 7 days were recorded. In all patients, bile and mesenteric lymph nodes samples were taken for bacterial growth and histopathologic changes were studied on the liver excised during surgery. RESULTS: In the control group, bacterial growth was observed in the bile and mesenteric lymph nodes cultures in one (7.1%) and two patients (14.3%), respectively. In the study group, 8 patients (42%) had positive bile cultures and 12 patients (63.2%) had positive mesenteric lymph nodes cultures, respectively. Histopathologic examination of the liver revealed significant increase in the rate of periductal and portal fibrosis in the jaundiced patients, compared with control group (p < 0.001). Postoperative complications in the study group were wound infection (3 cases), renal failure (2 cases), ARDS (1 cases) and intraabdominal abscess (1 cases). In the control group, one patient had wound infection and one had atelectasis. Two patients with jaundice died of multiple organ failure and respiratory failure. In long-term follow-up (mean 17 months), when sclerosing cholangitis and secondary biliary cirrhosis developed in one patient each in the study group, no long-term complication occurred in the control group. CONCLUSIONS: Our clinical results demonstrate that extrahepatic biliary obstruction promotes bacterial translocation and this process is an important cause of morbidity and mortality in patients with jaundice. Also, obstructive jaundice subsequently leads to significant functional and morphological damage in the liver.     

Effects of Lactobacillus plantarum on gut barrier function in experimental obstructive jaundice

AIM: To investigate the mechanisms of Lactobacillus plantarum (L. plantarum) action on gut barrier in preoperative and postoperative experimental obstructive jaundice in rats.METHODS: Forty rats were randomly divided into groups of sham-operation, bile duct ligation (BDL), BDL + L. plantarum, BDL + internal biliary drainage (IBD), and BDL + IBD + L. plantarum. Ten days after L. plantarum administration, blood and ileal samples were collected from the rats for morphological examination, and intestinal barrier function, liver function, intestinal oxidative stress and protein kinase C (PKC) activity measurement. The distribution and expression of the PKC and tight junction (TJ) proteins, such as occludin, zonula occludens-1, claudin-1, claudin-4, junction adhesion molecule-A and F-actin, were examined by confocal laser scanning microscopy, immunohistochemistry, Western blotting, real-time fluorescent quantitative polymerase chain reaction assay.RESULTS: L. plantarum administration substantially restored gut barrier, decreased enterocyte apoptosis, improved intestinal oxidative stress, promoted the activity and expression of protein kinase (BDL vs BDL + L. plantarum, 0.295 ± 0.007 vs 0.349 ± 0.003, P < 0.05; BDL + IBD vs BDL + IBD + L. plantarum, 0.407 ± 0.046 vs 0.465 ± 0.135, P < 0.05), and particularly enhanced the expression and phosphorylation of TJ proteins in the experimental obstructive jaundice (BDL vs BDL + L. plantarum, 0.266 ± 0.118 vs 0.326 ± 0.009, P < 0.05). The protective effect of L. plantarum was more prominent after internal biliary drainage ( BDL + IBD vs BDL + IBD + L. plantarum, 0.415 ± 0.105 vs 0.494 ± 0.145, P < 0.05).CONCLUSION: L. plantarum can decrease intestinal epithelial cell apoptosis, reduce oxidative stress, and prevent TJ disruption in biliary obstruction by activating the PKC pathway.     

Ultrasound in obstructive jaundice

One hundred and twenty-five consecutive patients with obstructive jaundice were prospectively studied by ultrasonography to determine the level and cause of obstruction. These were diagnosed precisely in 80 (72%) and 52 patients (41.6%) respectively. The results were compared with cholangiography. The final diagnosis was established at surgery (97 cases) and fine needle aspiration cytology (28 cases). While US is an excellent screening modality in distinguishing obstructive and non-obstructive jaundice, cholangiography is still the gold standard for determining the precise anatomic level and cause of obstruction.     

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.     

Effects of vitamin E on neutrophil phagocytosis during experimental obstructive jaundice

BACKGROUNDS/AIMS: Depression of non-specific immunity is one of the systemic complications of biliary obstruction. Vitamin E, which decreases during prolonged obstructive jaundice, may be beneficial to diseased function of neutrophils. In this study we want to investigate changes in neutrophil phagocytosis and the effect that vitamin E supplementation has on this function METHODOLOGY: Rats were divided into 5 groups as follows: the control group and 4 other groups that underwent double ligation and division of the common bile duct. Two of these 4 groups (Group 3 and 5) received vitamin E during the experiment. Alkaline phosphatase, aspartate aminotransferase, bilirubin serum levels, white blood cell count and neutrophil phagocytosis index were determined for group 2 and 3 at the end of the 15 days and for group 1, 4 and 5 at the end of the 21 days. RESULTS: There was a significant increase in white blood cell counts and biochemical parameters in group 2, 3, 4, and 5 (P < 0.05). Neutrophil phagocytosis index significantly increased 15 days after bile duct ligation (P < 0.001) (Group 2) and significantly decreased 21 days after bile duct ligation (P < 0.001) (Group 4). Neutrophil phagocytosis index in vitamin E pretreated groups were significantly decreased at the end of the 15 days (P < 0.001) (Group 3) and increased at the end of the 21 days (P < 0.001) (Group 5). CONCLUSIONS: Finally, If vitamin E is administered for further days and weeks of prolonged jaundiced, neutrophil phagocytosis index improves.     

Propolis reduces bacterial translocation and intestinal villus atrophy in experimental obstructive jaundice

AIM: To investigate the effects of propolis on bacterial translocation and ultrastructure of intestinal morphology in experimental obstructive jaundice. METHODS: Thirty Wistar-Albino male rats were randomly divided into three groups, each including 10 animals: group—effect on ileal mucosa and reduced bacterial translocation in the experimental obstructive jaundice model. Further studies should be carried out to explain the mechanisms of these effects.     

多巴胺调控实验性梗阻性黄疸围手术期肾髓质水通道蛋白2表达

目的:探讨梗阻性黄疸围手术期应用小剂量多巴胺对肾髓质水通道蛋白2(aquaporin 2)蛋白表达影响.方法:♂wistar大鼠70只随机分为4组,分别为对照组(n=10)、梗阻性黄疸组(n=20)、多巴胺5μg组(n=20)和多巴胺10μg组(n=20).梗阻性黄疸组及多巴胺组大鼠全身麻醉后建立梗阻性黄疸动物模型;对照组大鼠行假手术.7d后全麻下解除胆管梗阻,对照组再次行假手术.多巴胺组于胆管再通手术之前于股静脉套管针穿刺泵入多巴胺,剂量分别为5μg/(kg·min)和10μg/(kg·min);而假手术组及梗阻性黄疸组大鼠泵入9g/L生理盐水,泵注持续2h,并将各组动物随机均分为立即取材组和24h后取材组.腔静脉血离心后收集血清冻存检测胆红素、肌酐和尿素氮;分离肾脏髓质冻存,免疫印迹法(Western blotting)法检测aquaporin 2的表达.结果:解除梗阻早期鼠血清胆红素水平下降.血尿素氮及肌酐未见明显改变.通过Western blotting对肾髓质aqp2表达测定发现,梗阻性黄疸组解除梗阻0h取材组aqp2表达较对照组明显下降(15 665±1181 vs 21 966±1544,P<0.01),而解除梗阻24h后aqp2表达出现明显上升(36 490±1822 vs 21 917±2661,P<0.01).多巴胺5μg组0与24h aqp2表达更接近CO组(16 010±646,22 715±575 vs 21 966±1544,21 917±2661);10μg组各时间点aqp2表达与梗黄组接近(13 581±1662,32 313±1453 vs 15 665±1181,36 490±1822),未见多巴胺有明显调节aqp2表达作用.结论:胆管梗阻损伤肾脏集合管上皮细胞结构并抑制水重吸收功能;低浓度多巴胺可调控集合管水通道蛋白2表达.     

金属和塑料支架置入治疗胰头癌伴阻塞性黄疸的疗效分析

目的 分析比较金属与塑料胆管支架治疗胰头癌伴阻塞性黄疸的疗效.方法 40例胰头癌伴阻塞性黄疸患者随机分为2组,内镜下分别置入金属支架和塑料支架.观察术前和术后患者发热、腹痛、腹胀、黄疸、WBC、血淀粉酶、总胆红素(TB)、直接胆红素(DB)、ALT、AST、γ-GT、AKP的变化.结果 所有患者支架置入成功,术后1个月及6个月X线复查,提示支架仍保持原位及良好的扩张状态.术后发热、腹痛、腹胀、黄疸发生率明显降低(P＜0.05),WBC、TB、DB、ALT和AST也明显降低(P＜0.05).金属支架组发热、黄疸的发生率显著低于塑料支架组(P＜0.05),血胆红素、AKP、ALT水平也较塑料支架组显著降低(P＜0.05).但金属支架组术后3 h血淀粉酶升高较塑料支架组明显(P＜0.05).随访6月患者未出现死亡.结论 胆管支架能有效治疗胰腺癌伴阻塞性黄疸,金属支架的疗效显著优于塑料支架,但其术后发生胰腺炎的风险增高.