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Concept: Bilirubin

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BACKGROUND: Cichorium glandulosum Boiss. et Huet is used for treatment of liver disorders, and its effects are attributed to sesquiterpenes. This study aims to investigate the hepatoprotective effects of a sesquiterpene-rich fraction (SRF) from the aerial part of C. glandulosum on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in mice, and on priming with Bacillus Calmette–Guerin (BCG) followed by lipopolysaccharide (LPS)-induced immunological liver injury in mice. METHODS: SRF was suspended in water and administered to mice at 0.05, 0.10 and 0.20 g/kg body weight for 7 consecutive days. An active control drug (bifendate pills) was suspended in distilled water and administered to mice at 0.40 g/kg body weight for 7 consecutive days. Hepatotoxicity was induced by intraperitoneal injection of 0.1% CCl4 (0.2 mL/mouse) at 13 h before the last drug administration, or by tail intravenous injection of BCG (0.2 mL/mouse) before the first drug administration and LPS (0.2 mL/mouse; 8 mug) at 15 h before the last drug administration. Blood samples and the livers were collected for evaluation of the biochemical parameters of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (TBIL). RESULTS: SRF significantly reduced the impact of CCl4 toxicity. The highest dose of SRF (0.20 g/kg) was the most effective, reflected by significant reductions in the levels of AST (P = 0.001), ALT (P = 0.000) and TBIL (P = 0.009). The serum enzymatic levels induced by BCG and subsequent LPS injection were significantly and dose-dependently restored by SRF, reflected by significant reductions in the levels of AST (P = 0.003), ALT (P = 0.003) and TBIL (P = 0.007) for the highest dose of SRF (0.20 g/kg). CONCLUSION: SRF is hepatoprotective in animal models of chemical and immunological acute liver injury.

Concepts: Liver, Liver function tests, Aspartate transaminase, Alanine transaminase, Hepatology, Bilirubin, Hepatotoxicity, Chemical pathology

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BACKGROUND: Hyperbilirubinemia is emerging as an increasingly common problem in newborns due to a decreasing hospital length of stay after birth. Jaundice is the most common disease of the newborn and although being benign in most cases it can lead to severe neurological consequences if poorly evaluated. In different areas of medicine, data mining has contributed to improve the results obtained with other methodologies.Hence, the aim of this study was to improve the diagnosis of neonatal jaundice with the application of data mining techniques. METHODS: This study followed the different phases of the Cross Industry Standard Process for Data Mining model as its methodology.This observational study was performed at the Obstetrics Department of a central hospital (Centro Hospitalar Tamega e Sousa – EPE), from February to March of 2011. A total of 227 healthy newborn infants with 35 or more weeks of gestation were enrolled in the study. Over 70 variables were collected and analyzed. Also, transcutaneous bilirubin levels were measured from birth to hospital discharge with maximum time intervals of 8 hours between measurements, using a noninvasive bilirubinometer.Different attribute subsets were used to train and test classification models using algorithms included in Weka data mining software, such as decision trees (J48) and neural networks (multilayer perceptron). The accuracy results were compared with the traditional methods for prediction of hyperbilirubinemia. RESULTS: The application of different classification algorithms to the collected data allowed predicting subsequent hyperbilirubinemia with high accuracy. In particular, at 24 hours of life of newborns, the accuracy for the prediction of hyperbilirubinemia was 89%. The best results were obtained using the following algorithms: naive Bayes, multilayer perceptron and simple logistic. CONCLUSIONS: The findings of our study sustain that, new approaches, such as data mining, may support medical decision, contributing to improve diagnosis in neonatal jaundice.

Concepts: Pregnancy, Childbirth, Infant, Fetus, Bilirubin, Data mining, Pediatrics, Neonatal jaundice

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Steatotic grafts are excluded for use in partial liver transplantation (LT) due to increased risk of primary non-function. This study investigated the effects of suramin, a polysulfonated naphthylurea, on the outcome of steatotic partial LT. Rat livers were harvested after acute ethanol treatment (6 g/kg, i.g.), reduced in size to ~1/3, and transplanted. Serum alanine aminotransferase (ALT) and total bilirubin, and hepatic necrosis and apoptosis were significantly higher after transplantation of fatty partial grafts (FPG) than lean partial grafts (LPG). Suramin (5 mg/kg, i.p.) decreased ALT by ~60%, hyperbilirubinemia by 75%, necrosis by 83%, and apoptosis by 70% after FPG transplantation. Hepatic cellular 5-bromo-2'-deoxyuridine (BrdU) incorporation increased to 28% in LPG but was only 2% in FPG at 48 h and mitotic index increased to 7% in LPG but was only 0.2% in FPG, indicating suppressed regeneration in FPG. Suramin increased BrdU incorporation and mitotic index to 43% and 9%, respectively, in FPG. All FPG recipients died within 5 days. Suramin recovered survival of FPG to 62%. TNFα mRNA was 2.2-fold higher in FPG than in LPG and was associated with activation of caspase-8 and -3 in FPG. Suramin decreased TNFα and caspase activation in FPG. TGF-β, phospho-Smad2/3 and p21Cip1 were significantly higher in FPG than in LPG and suramin blocked TGF-β formation and its down-stream signaling pathway. Taken together, suramin improves the outcome of FPG transplantation, most likely by inhibition of TNFα and TGF-β formation.

Concepts: Apoptosis, Cirrhosis, Liver, Liver function tests, Alanine transaminase, Hepatology, Bilirubin, Jaundice

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BACKGROUND: Elevated Glasgow Prognostic Score (GPS) has been related to poor prognosis in patients with hepatocellular carcinoma (HCC) undergoing surgical resection or receiving sorafenib. The aim of this study was to investigate the prognostic value of GPS in patients with various stages of the disease and with different liver functional status. METHODS: One hundred and fifty patients with newly diagnosed HCC were prospectively evaluated. Patients were divided according to their GPS scores. Univariate and multivariate analyses were performed to identify clinicopathological variables associated with overall survival; the identified variables were then compared with those of other validated staging systems. RESULTS: Elevated GPS were associated with increased asparate aminotransferase ( P<0.0001), total bilirubin ( P<0.0001), decreased albumin (P<0.0001), alpha-fetoprotein ( P=0.008), larger tumor diameter ( P=0.003), tumor number ( P=0.041), vascular invasion ( P=0.0002), extra hepatic metastasis ( P=0.02), higher Child-Pugh scores (P<0.0001), and higher Cancer Liver Italian Program scores (P<0.0001). On multivariate analysis, the elevated GPS was independently associated with worse overall survival. CONCLUSIONS: Our results demonstrate that the GPS can serve as an independent marker of poor prognosis in patients with HCC in various stages of disease and different liver functional status.

Concepts: Cancer, Lung cancer, Cirrhosis, Liver, Multivariate statistics, Bilirubin, Prognosis, Jaundice

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Background Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. Methods In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. Results Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. Conclusions Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524 ; Current Controlled Trials number, ISRCTN89514817 .).

Concepts: Clinical trial, Cirrhosis, Liver, Hepatology, Bilirubin, Primary biliary cirrhosis, Primary sclerosing cholangitis, Jaundice

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Liver cirrhosis is a large burden on global health, causing over one million deaths per year. Observational studies have reported an inverse association between coffee and cirrhosis.

Concepts: Scientific method, Cirrhosis, Liver, Bilirubin, Hepatitis C, Hepatic portal vein, Liver transplantation, Names of large numbers

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Background Sequelae of severe neonatal hyperbilirubinemia constitute a substantial disease burden in areas where effective conventional phototherapy is unavailable. We previously found that the use of filtered sunlight for the purpose of phototherapy is a safe and efficacious method for reducing total bilirubin. However, its relative safety and efficacy as compared with conventional phototherapy are unknown. Methods We conducted a randomized, controlled noninferiority trial in which filtered sunlight was compared with conventional phototherapy for the treatment of hyperbilirubinemia in term and late-preterm neonates in a large, urban Nigerian maternity hospital. The primary end point was efficacy, which was defined as a rate of increase in total serum bilirubin of less than 0.2 mg per deciliter per hour for infants up to 72 hours of age or a decrease in total serum bilirubin for infants older than 72 hours of age who received at least 5 hours of phototherapy; we prespecified a noninferiority margin of 10% for the difference in efficacy rates between groups. The need for an exchange transfusion was a secondary end point. We also assessed safety, which was defined as the absence of the need to withdraw therapy because of hyperthermia, hypothermia, dehydration, or sunburn. Results We enrolled 447 infants and randomly assigned 224 to filtered sunlight and 223 to conventional phototherapy. Filtered sunlight was efficacious on 93% of treatment days that could be evaluated, as compared with 90% for conventional phototherapy, and had a higher mean level of irradiance (40 vs. 17 μW per square centimeter per nanometer, P<0.001). Temperatures higher than 38.0°C occurred in 5% of the infants receiving filtered sunlight and in 1% of those receiving conventional phototherapy (P<0.001), but no infant met the criteria for withdrawal from the study for reasons of safety or required an exchange transfusion. Conclusions Filtered sunlight was noninferior to conventional phototherapy for the treatment of neonatal hyperbilirubinemia and did not result in any study withdrawals for reasons of safety. (Funded by the Thrasher Research Fund, Salt Lake City, and the National Center for Advancing Translational Sciences of the National Institutes of Health; Clinical Trials.gov number, NCT01434810 .).

Concepts: Infant, Randomized controlled trial, Bilirubin, Efficacy, Pediatrics, Withdrawal, Neonatal jaundice, Crigler-Najjar syndrome

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A previously healthy man aged 50 years presented with malaise, anorexia, abdominal pain, nausea, vomiting, generalised jaundice, scleral icterus and dark urine. He was not on any prescription or over-the-counter medications, but reported drinking 4-5 energy drinks daily for 3 weeks prior to presentation. Physical examination revealed jaundice and right upper quadrant abdominal tenderness. Laboratory studies were remarkable for transaminitis and evidence of chronic hepatitis C infection. Ultrasound scan demonstrated an echogenic liver and diffuse gallbladder wall thickening. Liver biopsy showed severe acute hepatitis with bridging necrosis and marked cholestasis. The patient was treated supportively with complete resolution of his symptoms and marked improvement in his laboratory abnormalities. The development of acute hepatitis in this patient was likely secondary to excessive energy drink consumption. Energy drinks as well as other herbal/over-the-counter supplements should be considered by clinicians in the workup of patients with acute hepatitis, particularly once other aetiologies have been excluded.

Concepts: Cirrhosis, Hepatitis, Liver, Gastroenterology, Hepatology, Bilirubin, Hepatitis C, Jaundice

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Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often leading to end-stage liver disease. Its pathogenesis remains largely unknown, although frequent concomitant IBD hints towards common factors underlying gut and bile duct inflammation. Considering the mounting evidence on the involvement of the intestinal microbiota in initiating and determining IBD phenotype, we investigated intestinal microbiota composition in patients with PSC.

Concepts: Digestive system, Cirrhosis, Hepatology, Bilirubin, Bile, Cholestasis, Primary biliary cirrhosis, Primary sclerosing cholangitis

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We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P < 5 × 10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r(2) > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r(2) > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

Concepts: Immune system, Cirrhosis, United Kingdom, Hepatology, Bilirubin, Autoimmune disease, Primary biliary cirrhosis, Primary sclerosing cholangitis