Plasma Levels Of Total Bilirubin Research Articles

Quercetin prevents rats from type 1 diabetic liver damage by inhibiting TGF-ꞵ/apelin gene expression

BackgroundHyperglycemia-induced oxidative stress is a significant contributor to diabetic complications, including hepatopathy. The current survey aimed to evaluate the ameliorative effect of quercetin (Q) on liver functional disorders and tissue damage developed by diabetes mellitus in rats. MethodsGrouping of 35 male Wistar rats was performed as follows: sham; sham + quercetin (sham + Q: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage); diabetic control (Diabetes: streptozotocin (STZ), 65 mg/kg, i.p.); diabetic + quercetin 1 (D + Q1: quercetin, 25 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection); and diabetic + quercetin 2 (D + Q2: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection). Body weight, food intake, and water intake were measured. Ultimately, the samples of plasma and urine, as well as tissue samples of the liver and pancreas were gathered for later assays. ResultsSTZ injection ended in elevated plasma blood glucose levels, decreased plasma insulin levels, liver dysfunction (increased activity levels of AST, ALT, and ALP, increased plasma levels of total bilirubin, cholesterol, LDL, triglyceride, decreased plasma levels of total protein, albumin and HDL), enhanced levels of malondialdehyde, diminished activities of antioxidant enzymes (superoxide dismutase, and catalase), reduced level of glutathione (GSH) increased gene expression levels of apelin and TGF-ꞵ, plus liver histological destruction. All these changes were diminished by quercetin. However, the measure of improvement in the D + Q2 group was higher than that of the D + Q1 group. ConclusionsQuercetin improved liver function after diabetes mellitus type 1, possibly due to reduced lipid peroxidation, increased antioxidant systems, and inhibiting the apelin/TGF-ꞵ signaling pathway.

Addiction and the Risk of Common Bile Duct Stones: A 4-Year Retrospective Population-Based Study in Mashhad, Iran.

As a common digestive disorder, choledocholithiasis can have serious consequences, including death. Given that opioids have been shown to contribute to the spasm of Oddi's sphincter, which results in biliary stasis in the common bile duct (CBD), it is likely that opioids can also raise the prevalence of choledocholithiasis. In this regard, this study aimed to investigate how common opium addiction was among choledocholithiasis patients in Mashhad, Iran. The current retrospective observational study was conducted on 599 patients with choledocholithiasis who underwent endoscopic retrograde cholangiopancreatography (ERCP), utilizing information gathered at the Ghaem hospital in Mashhad, Iran, between 2011 and 2015. Patient data were collected from files and records using certain criteria such as gender, opium addiction, hepatic enzymes (AST, ALT, ALP), plasma levels of total bilirubin, and direct bilirubin. The size of the CBD stones as well as the correlation between the gallbladder and CBD stones were calculated. From among 599 patients included, 345 (57.6%) were female and 254 (42.4%) were male. Moreover, 195 patients (32.2%) had opiate addictions. The size of the CBD stone was correlated with the patient's age (r=0.17, P=0.001). The average stone measured 12.22±3.32 mm. There were notable differences in the mean size of the CBD stone (P<0.001) between addicted and non-addicted cases; specifically, the mean CBD stone size in addicted cases was 12.715.13 mm while it was 12.34.33 mm in non-addicted cases. This study showed patients with CBD stones have a higher rate of opium addiction compared to the general population, indicating a possible link between the two conditions.

Gvhd Targets Organoid-Forming Biliary Epithelial Stem Cells Via a TGF-β-Dependent Manner

[Introduction] Graft-versus-host disease (GVHD) is a potentially life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). We and others have shown that GVHD targets adult tissue stem cells in the gut and skin, while a role of liver tissue stem cells in hepatic GVHD remains to be clarified. Biliary epithelial cells (BECs) are primary targets in hepatic GVHD and a single BEC stem cell gives rise to multipotent liver organoids (Cao W: Gastroenterology 2017). We studied the fate and role of BEC stem cells in experimental hepatic GVHD. [Methods] B6D2F1 recipients were lethally irradiated and transplanted with 5 x 10 6 splenocytes plus 5 x 10 6 bone marrow cells from allogeneic (B6) or syngeneic (B6D2F1) donors on day 0. Liver organoids were generated from the bile ducts isolated from the liver right lobe. [Results] Flowcytometric analyses of the liver demonstrated donor T cell infiltration in the liver within the first week after allo-HCT, followed by massive infiltration of monocytes and macrophages. Hepatic GVHD was characterized by apoptosis of BEC (Figure 1A), elevated expression of Mmp7, a biomarker of biliary injury (Figure 1B), and elevation of plasma levels of total bilirubin (Figure 1C). To evaluate fate of BEC stem cells in hepatic GVHD, we enumerated BEC-derived organoids generated from the right lobe of the liver isolated after allo-HCT. The organoid-forming BEC stem cells were profoundly reduced at later time point after allo-HCT (Figure 1D), while they persisted in syngeneic controls, indicating that GVHD targets BEC stem cells. Next, we explored the mechanism of BEC stem cell injury. Among the cytokines elevated in the liver after allo-HCT, we found that TGF-β, not IFN-γ or TNF-α, inhibited generation of liver organoids (Figure 1E). Furthermore, we found that liver infiltrating mononuclear cells isolated from the allogeneic livers, not from syngeneic livers, suppressed growth of liver organoids. This effect was abrogated by the addition of a TGF-β inhibitor, SB-431542 in culture. Among these cells, monocyte-derived macrophages, not Kupffer cells, demonstrated enhanced production of TGF-β after allo-HCT (Figure 1F), suggesting that TGF-β from inflammatory macrophages damaged BEC stem cells. Based on these findings, we next tested if TGF-β inhibition could protect BEC stem cells and ameliorate hepatic GVHD after allo-HCT. Admnistration of SB-431542 from day +14 to day +28 after allo-HCT significantly increased organoid-forming BEC stem cells, suppressed BEC apoptosis and Mmp7 expression, and mitigated jaundice on day +28 after allogeneic HCT, indicating that TGF-β inhibition is a novel therapeutic strategy against hepatic GVHD (Figure 1, G-J). [Conclusion] Our results for the first time demonstrated that hepatic GVHD targets BEC stem cells via a TGF-β-dependent manner. Mmp7 and organoid-forming capacity could be the biomarkers for hepatic GVHD. BEC stem-cell protection by TGF-β inhibition is a promising novel therapeutic strategy against hepatic GVHD.Figures1: (A) Proportion of cleaved caspase 3 (cCaspase3) + cells among the biliary epithelial cells (BECs) on day +28. (B) Total RNA extracted from the liver on day +28 was subjected to Q-PCR targeting Mmp7. (C) Plasma levels of total bilirubin at indicated time points. (D) The numbers of organoid derived from the right lobe of the liver at indicated time point are shown. (E) Absolute numbers of TGF-β producing Kupffer cells and macrophages (Mφ) in the liver on day +28 are shown. (F) Liver organoids were enumerated after incubation in the presence or absence of TGF-β for 4 days. (G-J) Allogeneic recipients were intraperitoneally injected with 5 mg/kg SB-431542 daily from day +14 to day +28 after allogeneic HCT, and recipient mice were sacrificed on day +28. Numbers of organoids derived from the right lobe of the livers (G), the proportion of cCaspase3 + BECs (H), relative expression of Mmp7 in the liver (I), and plasma levels of total bilirubin (J) are shown. *; p < .05, **; p < .01, ***; p < .005. [Display omitted] DisclosuresTeshima: CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Gentium/Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Honoraria; Sanofi S.A.: Research Funding; TEIJIN PHARMA Limited: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fuji pharma CO.,Ltd: Research Funding; Pfizer Inc.: Honoraria; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Janssen Pharmaceutical K.K.: Other.

Abstract 17532: Impact of High Hepatic Wedge Pressure, Portal Hypertension, on Hemodynamics and Liver Function in Patients After the Fontan Operation

Background: Fontan circulation may be, in part, characterized by portal hypertension that can be estimated by hepatic vein wedge pressure (HWP). Purpose: To evaluate associations of HWP in cosecutive 318 Fontan patients (18±7 years old) during catheterization and compared the results with the hemodynamics, liver function and the related plasma biomarkers. HWP significantly correlated positively with inferior vena cava pressure (IVCP), pulmonary artery resistance (Rp), ration of Rp to systemic artery resistance (Rs) (Rp/Rs), and cardiac index and negatively with Rs and arterial and mixed venous oxgen saturations. Of those, high IVCP, low Rp and high Rp/Rs were independently correlated with high HWP (p&lt;0.05 for all). As for the liver function, HWP significantly correlated positively with plasma levels of total bilirubin (TB), hyaluronic acid, and type IV collagen (TyIV) and negatively with plasma levels of albumin and cholinesterase (ChE). Of those, ChE, TB and TyIV were independently correlated with high HWP (p&lt;0.01 for all). High HWP, low ChE, and high TyIV significantly correlated with high plasma nitric oxide products (p&lt;0.01). Conclusion: High HWP associates with a significant reduction of Rp and Rs with preserved cardiac output. This unique Fontan circulation with Rs-dominant reduction may be due to both portal hypertension and overproduction of nitric oxide secondary to liver dysfunction.

Biochemical indices of liver function in malaria patients

Introduction:Malaria is a tropical disease, which has hepatocellular involvement and is a significant cause of morbidity and mortality especially among children. Objective: This study investigated the biochemical indices of liver function in children with malaria and compared their results with healthy children (age and sex-matched). Methodology: Fifty patients (age: 5.1 ± 1.9 years) were enrolled from the Pediatrics’ clinic of a tertiary health institution in Ogun state, Nigeria. Fifty age- and sex- matched apparently healthy children, from the same geographical location were selected as controls. A thick film microscopy was used to confirm the presence of Plasmodium falciparum trophozoite in patients and its absence in controls. The in vitro determinations of the plasma activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), plasma total and conjugated bilirubin were performed using standard methods. Data obtained were statistically analyzed using student’s t-test and P<0.05 was considered significant. Results: The plasma activities of AST (34 ± 28 vs 10 ± 4 U/L) and plasma levels of total bilirubin (1.1 ± 0.7 vs 0.6 ± 0.2 mg/dL) were significantly higher in malaria patients compared with controls (p < 0.001). There was no significant difference in the plasma activities of ALT and ALP as well as concentration of conjugated bilirubin when compared with controls. Conclusion: This study revealed that abnormal biochemical indices of liver function observed in malaria patients does not conclusively imply liver disease, it could be as a result of intravascular haemolysis. Key words: Plasmodium falciparum , Malaria, Bilirubin, Liver enzymes.

Oxidative Stress and Paraoxonase Activity in Experimental Selenosis: Effects of Betaine Administration

The present study was undertaken on male rats to elucidate the selenosis induced by sodium selenite and the role played by betaine in alleviating selenium toxicity. Rats were treated with sodium selenite (6 mg/kg body weight/day) with or without betaine (240 mg/kg body weight/day). Selenotoxicosis was evident from the elevated plasma levels of total bilirubin, transaminases, and alkaline phosphatase activities. Moreover, the total protein levels decreased, and this decrease associated with a decreased albumin level, whereas the globulin level increased in selenium-intoxicated rats. The development of selenosis corresponded well with the induction of oxidative stress evident from decrease of total thiol level and glutathione content. Furthermore, activities of glutathione reductase, glucose-6-phosphate dehydrogenase, catalase, and paraoxonase-1 were decreased in selenium-treated rats. In contrast, superoxide dismutase and glutathione peroxidase activities were increased by excess selenium administration compared with control animals. As well, malondialdehyde and protein carbonyl were elevated in rats treated with selenium. Supplementation of betaine simultaneously with selenium caused less marked alteration in the investigated parameters. Betaine attenuated the selenotoxicosis by restoring thiol levels that preserve enzymatic antioxidants activity and attenuate the oxidation of lipids and proteins.

Analysis of the clinical features of and responsive factors on the prognosis in patients with fulminant hepatic failure

To judge the prognosis in the patients with fulminant hepatic failure and to provide the evidences of correct therapy. The clinical features and the indexes which may affect the prognosis of the patients with fulminant hepatic failure were analyzed. Indexes including prothrombin time (PT), the routine biochemical analysis of liver and kidney functions, the plasma levels of glucose and ammonia, cortisol, lipases, amylase, age, gender and complications were analyzed using the software Statistical Product and Service Solutions (SPSS)15.0. The differences between the died and living patients were compared. The mortality of the patients was 65% and the highest was 80% for those with HBV and HEV coinfection. The age and gender had no influence on mortality (P value was 0.423 and 0.728 respectively). HBV infection was the main factor which caused fulminant hepatic failure (52%), The next was hepatitis E virus infection (39%). Among the indexes analyzed, the plasma levels of total bilirubin, usea nitrogen, creatinine, glucose, cholesterol and prothrombin time had positive correlations with the prognosis of the patients (P value was 0.005, 0.001, 0.001, 0.005, 0.010 and 0.049 respectively). The incidence rate of hepatic coma, hepatorenal syndrome, and adrenal insufficiency were higher in the died group than that in the living group (P value was 0.005, 0.012 and 0.025 respectively). But prothrombin time was the only factor which had correlation with the prognosis (P=0.035) analyzed by multivariate logistic regression analysis. The scores of MELD were higher in the died group than that in living group (t=18.236, P<0.01) and especially in the patients with hepatic coma and hepatorenal syndrome. The scores of MELD also had positive correlation with the plasma level of TNFa (r=0.585, P<0.01). The HBV infection was the main cause of fulminant hepatic failure and HBV and HEV coinfection had the highest mortality. The plasma levels of total bilirubin, cholesterol, glucose , prothrombin time and some complications including hepatic coma, hepatorenal syndrome, and adrenal insufficiency maybe had positive correlations with the prognosis of fulminant hepatic failure. The scores of MELD may predict the prognosis of these patients.

Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide‐induced fulminant hepatic failure: Role of nitric oxide synthase isoforms

Hepatic encephalopathy is a complex neuropsychiatric syndrome. A previous study showed that chronic nitric oxide (NO) inhibition aggravated the severity of encephalopathy in thioacetamide (TAA)-treated rats. The present study investigated the relative contribution of NO synthase (NOS) isoforms on the severity of hepatic encephalopathy in TAA-treated rats. Fulminant hepatic failure was induced in male Sprague-Dawley rats by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Rats were divided into three groups to receive N(omega)-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor, 25 mg/kg/day in tap water), L-canavanine (an inducible NOS inhibitor, 100 mg/kg/day via intraperitoneal injection) or normal saline (N/S) from 2 days prior to TAA administration and lasting for 5 days. Severity of encephalopathy was assessed by the counts of motor activity. Plasma levels of tumor necrosis factor-alpha (TNF- alpha) were determined by enzyme-linked immunosorbent assay (ELISA), and total bilirubin, alanine aminotransferase (ALT) and creatinine were determined by colorimetric assay. Compared with L-canavanine or N/S-treated rats (0% and 4%, respectively), the mortality rate was significantly higher in rats receiving L-NAME administration (29%, P < 0.005). Inhibition of NO created detrimental effects on the counts of motor activities (P < 0.05). Rats treated with L-NAME had significantly higher plasma levels of total bilirubin, ALT, creatinine and TNF- alpha as compared with rats treated with L-canavanine or N/S (P < 0.01). Chronic L-NAME administration, but not L-canavanine, had detrimental effects on the severity of hepatic damage and motor activities in TAA-treated rats. These results suggest that constitutive NOS activities play a major protective role in rats with fulminant hepatic failure.

Extracorporeal liver support based on primary human liver cells and albumin dialysis – treatment of a patient with primary graft non-function

Methods: Following liver transplantation, a 26-year old female suffered from primary non-function of the transplant. The patient was subsequently treated with a modular extracorporeal liver support concept until a suitable organ became available. A bioreactor was charged with human liver cells, obtained from a discarded cadaveric graft (470 g, viability: 60%). The bioreactor was integrated into an extracorporeal circuit with continuous single pass albumin dialysis and continuous veno-venuous hemodiafiltration for detoxification and fluid reduction. Results: Over the total system application time of 79 h, a significant reduction of the plasma levels of total bilirubin (21.1 mg/dl at start, 10.1 mg/dl at end of therapy) and ammonia (100 versus 22.7 μmol/l) was achieved. During treatment the patient's neurological status significantly improved from coma stage IV to I permitting extubation. Recovery of kidney function with a urine output of 1325 ml/24 h compared to 45 ml/24 h prior to system application, was noted. Over the treatment period, an improvement of coagulation status was observed. Adverse events were absent. Conclusions: This first successful clinical treatment of a patient with liver failure suggests that a modular approach combining both primary human liver cell bioreactor technology and detoxification methods is promising.