Reduction In Total Bilirubin Research Articles

Licorice and liver function in patients with primary liver disease: A systematic review and meta-analysis of RCTs.

Licorice (Glycyrrhiza spp.) has been a cornerstone of traditional Chinese and Japanese medicine. This systematic review and meta-analysis aimed to evaluate the efficacy of licorice formulations, alone or in combination with other herbs, on liver function enzymes in patients with primary liver disease. We systematically searched MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library up to April 2024. Randomized controlled trials (RCTs) comparing the effects of Glycyrrhiza spp. preparations versus placebo or standard of care controls were included. Standard Cochrane methods were used to extract data and appraise eligible studies. A total of 15 RCTs, involving 1367 participants, were included in the analysis. The studies varied widely in geographical location, duration, and licorice preparations used. Licorice significantly reduced alanine aminotransferase (ALT) by 15.63 U/L (95% CI: -25.08, -6.18; p = 0.001) and aspartate aminotransferase (AST) by 7.37 U/L (95% CI: -13.13, -1.61; p = 0.01) compared to control groups. Subgroup analyses revealed that purified glycyrrhizic acid compounds were particularly effective, showing greater reductions in ALT and AST without significant heterogeneity. Although licorice treatment did not significantly impact gamma-glutamyl transferase and total bilirubin (TBIL) levels overall, specific licorice-herb preparations did show a notable reduction in TBIL. The safety profile of licorice was consistent with known side effects, predominantly mild and related to its mineralocorticoid effects. Despite heterogeneity and potential language bias, the findings suggest that licorice can enhance liver function. Further studies should standardize licorice preparations and explore its role in multifaceted herbal formulations to better understand its hepatoprotective mechanisms.

Hemoadsorption Therapy for Critically Ill Patients with Acute Liver Dysfunction: A Meta-Analysis and Systematic Review.

Critically ill patients are at risk of developing acute liver dysfunction as part of multiorgan failure sequelae. Clearing the blood from toxic liver-related metabolites and cytokines could prevent further organ damage. Despite the increasing use of hemoadsorption for this purpose, evidence of its efficacy is lacking. Therefore, we conducted this systematic review and meta-analysis to assess the evidence on clinical outcomes following hemoadsorption therapy. A systematic search conducted in six electronic databases (PROSPERO registration: CRD42022286213) yielded 30 eligible publications between 2011 and 2023, reporting the use of hemoadsorption for a total of 335 patients presenting with liver dysfunction related to acute critical illness. Of those, 26 are case presentations (n = 84), 3 are observational studies (n = 142), and 1 is a registry analysis (n = 109). Analysis of data from individual cases showed a significant reduction in levels of aspartate transaminase (p = 0.03) and vasopressor need (p = 0.03) and a tendency to lower levels of total bilirubin, alanine transaminase, C-reactive protein, and creatinine. Pooled data showed a significant reduction in total bilirubin (mean difference of -4.79 mg/dL (95% CI: -6.25; -3.33), p = 0.002). The use of hemoadsorption for critically ill patients with acute liver dysfunction or failure seems to be safe and yields a trend towards improved liver function after therapy, but more high-quality evidence is crucially needed.

Bilirubin adsorption versus plasma exchange for hyperbilirubinemia in patients after cardiac surgery: a retrospective study

ObjectiveHyperbilirubinemia after cardiac surgery increases in-hospital mortality and is associated with poor prognosis. Our present study aimed to compare the efficacy of bilirubin adsorption (BA) and plasma exchange (PEX) in patients with hyperbilirubinemia after cardiac surgery.MethodsWe retrospectively included patients who underwent BA treatment or PEX treatment due to severe hyperbilirubinemia after cardiac surgery at our center from 2015 to 2020. We collected results from urine and liver function tests before and after treatment and compared the in-hospital mortality and morbidity between the two treatment groups.ResultsA total of 56 patients were enrolled in this study: 14 patients received BA treatment, and 42 patients received PEX treatment. Compared to the PEX group, the BA group exhibited a statistically significant reduction in total bilirubin (p = 0.016) and direct bilirubin (p = 0.036) levels. The in-hospital mortality was 85.7% (48/56) in the whole group, and the BA group had a lower mortality than the PEX group (71.4% vs. 90.5%, p = 0.078). The BA group showed better circulatory support, including lower risks of IABP (21.4% vs. 52.4%, p = 0.044), ECMO (21.4% vs. 50.0%, p = 0.061), reintubation (64.3% vs. 40.5%, p = 0.122) and ventricular arrhythmias (64.3% vs. 45.2%, p = 0.217). The in-hospital mortality was still lower in the BA treatment group than in the PEX treatment group (71.4% vs. 100%, p = 0.049) in the matched cohort.ConclusionsCompared to PEX treatment, BA treatment had a higher bilirubin removal ability in patients with hyperbilirubinemia and could reduce the mortality and risks of poor clinical outcomes. BA treatment should be considered an effective treatment method for patients with higher total bilirubin or direct bilirubin levels.

Extracorporeal Albumin Dialysis in Liver Failure with MARS and SPAD: A Randomized Crossover Trial

Introduction: Liver failure is associated with hepatic and extrahepatic organ failure leading to a high short-term mortality rate. Extracorporeal albumin dialysis (ECAD) aims to reduce albumin-bound toxins accumulated during liver failure. ECAD detoxifies blood using albumin dialysis through an artificial semipermeable membrane with recirculation (molecular adsorbent recirculating system, MARS) or without (single-pass albumin dialysis, SPAD). Methods: We performed a randomized crossover open trial in a surgical intensive care unit. The primary outcome of the study was total bilirubin reduction during MARS and during SPAD therapies. The secondary outcomes were conjugated bilirubin and bile acid level reduction during MARS and SPAD sessions and tolerance of dialysis system devices. Inclusion criteria were adult patients presenting liver failure with factor V activity <50% associated with bilirubin ≥250 μmol/L and a complication (either hepatic encephalopathy, severe pruritus, or hepatorenal syndrome). For MARS and SPAD, the dialysis flow rate was equal to 1,000 mL/h. Results: Twenty crossovers have been performed. Baseline biochemical characteristics (bilirubin, ammonia, bile acids, creatinine, and urea) were not statistically different between MARS and SPAD. Both ECAD have led to a significant reduction in total bilirubin (−83 ± 67 μmol/L after MARS; −122 ± 118 μmol/L after SPAD session), conjugated bilirubin (−82 ± 61 μmol/L after MARS; −105 ± 96 μmol/L after SPAD session), and bile acid levels (−64 ± 75 μmol/L after MARS; −56 ± 56 μmol/L after SPAD session), all nondifferent comparing MARS to SPAD. Conclusion: A simple-to-perform SPAD therapy with equal to MARS dialysate flow parameters provides the same efficacy in bilirubin and bile acid removal. However, clinically relevant endpoints have to be evaluated in randomized trials to compare MARS and SPAD therapies and to define the place of SPAD in the liver failure care program.

Metabolic status of rabbits under physiological adaptation to cage husbandry technology

The article considers changes in biochemical blood parameters depending on the degree of adaptation process manifesting on the plantar surface of hind limbs of different sex rabbits and physiological state under cage husbandry technology. Groups of stud bucks (1st series), pregnant and lactating does (2nd and 3rd series of experiments) were formed according to the stages of structural changes depending on the stress of physiological regulatory processes of adaptation (the systematics proposed by R.M. Baevsky). The authors studied the following factors in serum: total protein, protein fractions (albumin, α-, β-, γ-globulin), creatinine, total bilirubin, urea, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, glucose triacylglycerol and cholesterol. At the stressed stage of regulatory systems the group of bucks showed a reduction of total bilirubin on the background of decrease of ALT, AST and alkaline phosphatase, which can testify to activation of liver function at this stage, and increase in bilirubin, ALT, AST with a simultaneous decrease in alkaline phosphatase, noted at the overstress stage of physiological adaptation regulatory processes, can testify to decrease in the functional activity of hepatocytes.Pregnant rabbits have the most pronounced compensatory reactions in the third stage of the adaptation process: the increase in absolute and relative γ-globulin values indicates the activation of immune factors. An increase in creatinine and urea levels during the gestation period, against a background of developing adaptive changes on the plantar surface of the feet, indicates a decrease in the filtration capacity of the renal tubules.Lactating animals experience an increased physiological load on the liver, which is expressed by an increase in triacylglycerols throughout the adaptation.

Preclinical evidence of Yinchenhao decoction on cholestasis: A systematic review and meta-analysis of animal studies.

Cholestasis is an important cause of liver fibrosis and cirrhosis. Yinchenhao decoction has been used as a well-known traditional Chinese medicine used in the treatment of cholestasis for over 2,000 years. The purpose of this systematic review is to evaluate the preclinical evidence of Yinchenhao decoction on cholestasis models. The following databases were searched from inception to February 2020. Chinese National Knowledge Infrastructure, VIP medicine information system, Wanfang Database, PubMed, Web of Science, Embase and the Cochrane Library were searched. The content concerned Yinchenhao decoction on different animal model experiments for the treatment of cholestasis. The methodological quality of the included studies was assessed based on the SYstematic Review Center for Laboratory animal Experimentation Animal Experiment Bias Risk Assessment Tool. A meta-analysis was conducted with RevMan 5.3 software according to the Cochrane tool. Nineteen studies on a total of 404 animals were included with five kinds of experimental animal models. The results showed that serum total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin and total bile acid in the group treated with Yinchenhao decoction were significantly lower than those in the model group (P < 0.00001). The alanine aminotransferase (ALT), aspartate aminotransferase and alkaline phosphatase levels in the Yinchenhao decoction group were also significantly reduced (P < 0.00001). The subgroup analysis of the different models showed that Yinchenhao decoction had a significant effect on the bile duct ligation model, and there was a significant reduction in TBIL, DBIL and ALT levels (P < 0.00001) in ANIT-induced cholestasis. After 24 hours of Yinchenhao decoction treatment, there was no significant difference in TBIL levels (P = 0.34), but after 48 and 72 hours of treatment, the TBIL levels were significantly reduced compared with the model group (P < 0.00001). There was no significant difference in DBIL after 48 hours of administration (P = 0.26), but compared with the model group, Yinchenhao decoction could significantly reduce the DBIL levels after 48 hours of treatment (P < 0.0003). Yinchenhao decoction could significantly reduce the ALT levels after 24, 48 and 72 hours (P < 0.006). Yinchenhao decoction was able to significantly reduce the levels of TBIL, DBIL and ALT on different rat species: Wistar and Sprague Dawley (P = 0.0001; P = 0.0002). The preclinical evidence indicated that Yinchenhao decoction might be a potent and promising agent for cholestasis. Moreover, this conclusion should be further confirmed with more well-designed researches.

Effect of Carbon Tetrachloride‑induced Hepatic Injury on Luffa acutangula (var.) Amara

Objectives: To study the reversal effect of carbon tetrachloride (CCl4)-induced hepatic injury on the ethyl acetate and ethanol extracts of Luffa acutangula var. amara in Wistar rats. Materials and Methods: The study included experimental mice groups in which pentobarbital-induced sleeping time and its prolongation by CCl4is assessed by righting reflex and recovery time. Chronic liver injury was induced by oral administration of CCl4and acute injury by a single intraperitoneal injection in experimental Wistar rats. Blood and liver specimens were used for analysis of enzymatic reactions. Results: It was noted that the mice groups treated with extracts decrease the sleeping time in and standard silymarin than the control group. Acute and chronic liver injury models showed increases in total protein and glutathione peroxidase, whereas there was a reduction in total bilirubin and serum alkaline phosphate level in extracts and standard silymarin-treated rats than control. Histopathological studies showed a significant reduction in inflammation, fatty change and gross necrosis in extracts and standard silymarin-treated animals than control. Conclusion: The study suggests that extracts of L. acutangula var. amara can be useful in treating acute and chronic hepatic injury.

Gemcitabine Plus Cisplatin Chemotherapy Prolongs the Survival in Advanced Hilar Cholangiocarcinoma: A Large Multicenter Study.

Gemcitabine plus cisplatin (GC) is recommended as first-line treatment for advanced cholangiocarcinoma. We investigated the impact of GC in patients with unresectable hilar cholangiocarcinoma (HC) based on the time taken for effective biliary drainage (EBD). We retrospectively enrolled 113 patients with unresectable HC. Thirty-nine and 74 patients received GC chemotherapy and best supportive care (BSC), respectively. EBD was defined as a reduction in total bilirubin >50% or to a value <2 mg/dL after the drainage procedure. Early EBD (eEBD) and delayed EBD (dEBD) were separated by 2 weeks. Overall survival (OS) was estimated. The GC group showed a significantly longer median OS than the BSC group (12.8 vs. 6.1 mo; P<0.001). Moreover, the eEBD group experienced a significantly longer OS than the dEBD group (8.2 vs. 4.3 mo; P<0.001). GC led to improved OS in the eEBD (12.8 vs. 6.8 mo; P=0.003) and dEBD (12.2 vs. 3.4 mo; P=0.009) groups. In multivariate analysis, dEBD (adjusted hazard ratio [aHR], 1.785; 95% confidence interval [CI], 1.183-2.691; P=0.006), BSC (aHR, 2.409; 95% CI, 1.579-3.675; P<0.001), and an ECOG status ≥2 (aHR, 3.721; 95% CI, 2.093-6.615; P<0.001) were associated with poor prognosis. In GC group, the older (70 y and above) patients did not have a higher risk of death than younger patients. GC prolongs the survival of patients with unresectable HC, even those with dEBD or elderly.

OPTIMUM DURATION OF PERCUTANEOUS TRANSHEPATIC CHOLANGIODRAINAGE IN COMMON BILE DUCT DISEASES COMPLICATED BY OBSTRUCTIVE JAUNDICE

The aim: Is to determine the optimum duration of percutaneous transhepatic cholangiodrainage depending on the duration of obstructive jaundice and the baseline total bilirubin level in patients with benign and malignant common bile duct diseases complicated by obstructive jaundice. Materials and methods: The experience of applying percutaneous transhepatic cholangiodrainage was combined for 88 patients with common bile duct diseases complicated by obstructive jaundice. The patients were divided into three groups: the Group 1 included 15 patients (17.1%) with benign common bile duct diseases, the Group 2 included 11 patients (12.5%) with resectable cholangiocarcinomas, and the Group 3 included 62 patients (70.4%) with unresectable cholangiocarcinomas. To determine optimal terms of biliary decompression using percutaneous transhepatic cholangiodrainage, the Poisson process was applied, and, to be more precise, the quasi-Poisson distribution. Results: It was found that the reduction of total bilirubin was the fastest in Group 3 patients. It took these patients an average of 7-8 days to reduce total bilirubin to 50 μmole/l. In Group 1 patients, the process is somewhat slower. The duration of biliary decompression in this category of patients averages 10-12 days. For Group 2 patients, biliary decompression requires at least 12 days. Conclusions: Using the Poisson process, or, to be more precise, the quasi-Poisson distribution, we managed to determine the optimum duration of biliary decompression using percutaneous transhepatic cholangiodrainage depending on the obstructive jaundice duration and the baseline total serum bilirubin.

Protective Role of Training and Selenium Consumption Against Renal Toxicity Induced by Cadmium in Rats

Background: Cadmium is a toxic metal, which can cause damage to the renal tissue. Various studies have suggested the protective role of training and selenium as a cofactor involved in the production of antioxidants in acute and chronic kidney disease, although the molecular-cellular mechanism of these two interventions is still not fully understood in the renal tissue. Objectives: The aim of this study was to investigate the protective effects of training and selenium consumption on the renal tissue of cadmium-poisoned rats. Methods: In this experimental study, 40 rats were randomly assigned into eight groups of five rats, including: (1) control, (2) sham, (3) cadmium, (4) cadmium + selenium, (5) cadmium + continuous training, (6) cadmium + high intensity interval training (HIIT), (7) cadmium + continuoustraining + selenium, and (8) cadmium + HIIT + selenium. During eight weeks, rats in groups 3 - 8 received 2 mg/kg of cadmium peritoneally daily and rats in groups 4, 7, and 8 received 0.23 mg/kg of selenium per day, peritoneally. Also, rats in groups 5 - 8 were given three sessions of HIIT (with 80 - 110 percentage of maximum speed) and continuous training (with 50% to 75% of maximum speed) for three sessions per week. Shapiro-Wilk, one-way ANOVA, two-way ANOVA, and Bonferroni’s post hoc tests were used to analyze the findings. The significance level was considered at 0.05. Results: Continuous training had a significant effect on reduction of albumin (ALB) (P = 0.001) and total bilirubin (TBIL) (P = 0.001), in addition, HIIT had a significant effect on reduction of ALB (P = 0.001) and TBIL (P = 0.04). The results of the two-way ANOVA test showed that selenium had a significant effect on the reduction of ALB (P = 0.001), TBIL (P = 0.001), and histidine ammonia-lyase (HAL) (P = 0.001). In addition, training with selenium had interactive effects on the reduction of TBIL (P = 0.004) and HAL (P = 0.001). Conclusions: It seems that continuous training and HIIT, along with selenium consumption, have protective effects on the renal tissue of cadmium-poisoned rats.

Efficacy of artichoke leaf extract in non-alcoholic fatty liver disease: A pilot double-blind randomized controlled trial.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and is potentially treatable, though there are few therapeutic agents available. Artichoke leaf extract (ALE) has shown potential as a hepatoprotective agent. This study sought to determine if ALE had therapeutic utility in patients with established NAFLD. In this randomized double-blind placebo-controlled parallel-group trial, 100 subjects with ultrasound-diagnosed NAFLD were randomized to either ALE 600mg daily or placebo for a 2-month period. NAFLD response was assessed by liver ultrasound and serological markers including the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and AST to platelet ratio index (APRI) score. Ninety patients completed the study (49 ALE and 41 placebo) with no side effects reported. ALE treatment compared with placebo: Doppler sonography showed increased hepatic vein flow (p<.001), reduced portal vein diameter (p<.001) and liver size (p<.001), reduction in serum ALT (p<.001) and AST (p<.001) levels, improvement in AST/ALT ratio and APRI scores (p<.01), and reduction in total bilirubin. ALE supplementation reduced total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and triglyceride concentrations (p=.01). This study has shown beneficial effects of ALE supplementation on both ultrasound liver parameters and liver serum parameters (ALT, AST, APRI ratio, and total bilirubin) in patients with NAFLD.

Endoscopic ultrasound-guided choledochoduodenostomy using partially-covered self-expandable metal stent in patients with malignant distal biliary obstruction and unsuccessful ERCP

Background and study aims Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) is an alternative to percutaneous transhepatic biliary drainage (PTBD) for patients with malignant distal biliary obstruction in whom ERCP has failed. We studied technical success, clinical success, stent patency rate and occurrence of adverse events in patients undergoing EUS-CDS with partially-covered self-expanding metal stent (PCSEMS). Patients and methods Medical records of consecutive patients with unresectable malignant distal biliary obstruction requiring biliary drainage who underwent EUS-CDS because of failure of attempt at ERCP were reviewed. EUS-CDS was done using 6-cm, PCSEMS (Wallflex, Boston Scientific). Technical success, clinical success (more than 50 % reduction in total bilirubin at 2 weeks post-procedure), stent patency rate and adverse events (AEs) were assessed. Patients were followed up for 3 months post-procedure. Results Between January 2015 and December 2016, 30 patients underwent EUS-CDS, including 20 (67 %) with failed biliary cannulation and 10 (33 %) with duodenal stenosis. Technical success was achieved in 28 patients, all of whom also had clinical success. Median total serum bilirubin decreased from 20 mg/dL to 5 mg/dL at 2 weeks post-procedure. Three patients (10 %) had adverse events (bile leak, hemobilia, stent block in one patient each; no stent migration); none of these adverse events was major and all were managed successfully. There were no procedure-related deaths. Five patients died of disease progression in the 3-month period post-procedure, and the 3-month dysfunction-free stent patency rate was 83 %. Conclusion EUS-CDS with a PCSEMS has a high technical and clinical success. Adverse events were infrequent, minor and could be managed easily.

Elevated serum urate is a potential factor in reduction of total bilirubin: a Mendelian randomization study.

AimA Mendelian randomization study (MRS) can be linked to a “natural” randomized controlled trial in order to avoid potential bias of observational epidemiology. We aimed to study the possible association between serum urate (SU) and total bilirubin (TBIL) using MRS.Materials and MethodsAn observational epidemiological study using ordinary least squares (OLS) regression and MRS using two-stage least square (TLS) regression was conducted to assess the effect of SU on TBIL. The comparison between the OLS regression and the TLS regression was analyzed by the Durbin-Hausman test. If the p value is significant, it suggests that the OLS regression cannot evaluate the relationship between exposure and outcome, and the TLS regression is precise; while if the p value is not significant, there would be no significant difference between the two regressions.ResultsA total of 3,753 subjects were analyzed. In OLS regression, there was no significant association between SU and TBIL in all subjects and subgroup analysis (all p > 0.05). However, MRS revealed a negative correlation between SU and TBIL after adjustment for confounders (beta = –0.021, p = 0.010). Further analysis was conducted in different SU subgroups, and results show that elevated SU was associated with a significant reduction in TBIL after adjustment for hyperuricemic subjects (beta = –0.053, p = 0.027). In addition, the results using the Durbin-Hausman test further confirmed a negative effect of SU on TBIL (p = 0.002 and 0.010, respectively).ConclusionsThis research shows for the first time that elevated SU was a potential causal factor in the reduction of TBIL and it provides strong evidence to resolve the controversial association between SU and TBIL.

Resolution of Jaundice in a Patient With Primary Biliary Cholangitis on Obeticholic Acid

Primary biliary cholangitis (PBC) is an autoimmune disease marked by destruction of small intralobular bile ducts. Without medical therapy, patients can develop cholestatic liver disease, cirrhosis, and even liver failure. First line therapy with ursodeoxycholic acid (UDCA) is often effective, but up to 35% of patients will experience a suboptimal response. Obeticholic acid (OCA) has been recently approved for use in patients with inadequate response to UDCA alone. In prior trials, the addition of OCA has been associated with significant improvement in alkaline phosphatase (ALP) but only minimal reduction in total bilirubin (Tbil). With this case, we present a patient with inadequate response to UDCA who demonstrated remarkable improvement with marked reduction in ALP and resolution of jaundice after the addition of OCA. A 62 year old female presented with jaundice and labs revealed elevated liver-associated enzymes (LAEs), notably ALP 912 and Tbil 3.9. PBC was diagnosed based on positive AMA and liver biopsy findings. Histology also noted stage 3 hepatic fibrosis. She was started on UDCA 500mg twice daily with initial improvement in ALP but not Tbil (Figure 1). MRCP revealed a questionable focal biliary stricture, although endoscopic stenting did not lead to biochemical improvement and no stricture was seen on subsequent imaging. Repeat liver biopsy confirmed PBC and excluded overlap of autoimmune hepatitis. Due to persistent jaundice, the patient was started on OCA 5mg daily in conjunction to her UDCA. After six months, ALP has slowly declined to 279, and other LAEs have normalized with Tbil 0.8. OCA is a novel agent farnesoid X receptor agonist and has direct anti-cholestatic and anti-fibrotic effects. The addition of OCA to UDCA is associated with a 20-25% reduction in ALP. While our patient had an expected decline in ALP, the more remarkable finding has been the complete resolution of her hyperbilirubinemia with the combination of UDCA and low dose OCA. Her Mayo risk score declined from intermediate to low risk of death (7.8 to 5.7). This unexpected clinical improvement has allowed us to continue medical management while deferring liver transplant evaluation. More long-term data are needed to determine whether OCA impacts overall and transplant-free survival in patients with PBC.

Evaluation of occupational exposure to metal dust on the liver of road construction workers in Abuja metropolis

Increasing air pollution levels due to rapid urbanization and growth in infrastructural facilities coupled with low level of standard safety procedures have been observed in Nigeria, and become a major source of concern. The study evaluated the effects of occupational exposure to metal dust on the liver of road construction workers in Abuja metropolis. Blood samples were used in the measurement of Lead, cadmium, magnesium and iron as indicators for metal toxicity. Bilirubin, liver enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatise (ALP)) and proteins as biomarkers for liver function. Samples were collected from different road construction sites. One hundred (n = 100) subjects were recruited and served as the exposed group and another one hundred (n = 100) control as unexposed (control) group. Samples were analyzed using Atomic Absorption Spectrometry for the toxic metals (Lead and Cadmium) and trace elements (Magnesium and Iron); and Selectra ProS Clinical Chemistry Auto Analyzer for the liver function tests respectively. This study showed a statistically significant increase in Lead, Magnesium and Iron (p<0.001) when exposed subjects were compared with unexposed subjects. Test for liver function showed a significant reduction in total bilirubin (p<0.01) and direct bilirubin (p<0.05) respectively. Albumin also show statistically significant increase (p<0.05) on comparison of exposed and unexposed subjects. This study indicates the presence of metal dust in road construction workers occupationally exposed, and suggestive of liver impairment following continued exposure to these toxic metals and trace elements. Key words: Occupational exposure, metal dust, liver.

Endoscopic ultrasound-guided choledochoduodenostomy for malignant distal biliary obstruction after failed endoscopic retrograde cholangiopancreatography with partially covered self-expanding metal stent

Background and Objectives:Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CD) is an alternative procedure to percutaneous transhepatic biliary drainage for patients with malignant distal biliary obstruction requiring biliary drainage in whom ERCP has failed. We studied technical success, clinical success, stent patency rate, and adverse events in EUS-CD.Methods:It is a prospective study from January 2015 to December 2016. Patients with unresectable, malignant distal biliary obstruction requiring biliary drainage in whom ERCP had failed either because of failed cannulation of papilla or due to duodenal stenosis were included. EUS-CD was done using a 6 cm partially covered self-expanding metal stent. Technical success, clinical success (more than 50% reduction in total bilirubin by week 2), stent patency rate, and adverse events were assessed. Patients were followed up for 3 months.Results:Thirty patients underwent EUS-CD, 20 (66.7%) had failed cannulation of papilla, and 10 (33.3%) had duodenal stenosis. EUS-CD was successfully done in 28 patients; all of those had clinical success. Total bilirubin (in median) decreased from 20 mg/dl to 5 mg/dl by week 2. Four patients (13.3%) had adverse events; two had bile leak, one had hemobilia, and other had stent block due to sludge. None had major adverse events; all adverse events were managed successfully. Five died due to progression of disease within 3 months (range: 40–88 days) with 3-month stent dysfunction-free patency rate of 83.33%. No procedure-related mortality occurred.Conclusion:EUS-CD with a partially covered metal stent has a high technical and clinical success with no major adverse events.

547. Untranslated Region Optimization Increases Transgene mRNA and Protein Levels, Resulting in Enhanced Therapeutic Efficacy of AAV Vector Gene Transfer In Vivo for Crigler-Najjar Syndrome

Optimization of the transgene expression cassette for adeno-associated virus (AAV) vector-mediated gene therapy has been mainly focused on the design of efficient promoter/enhancers and on the optimization of the transgene codon usage. Addition of intron sequences to expression cassette of a given transgene has also been shown to be beneficial in terms of expression levels.In an effort to develop a liver gene transfer approach to treat Crigler-Najjar (CN) syndrome, an autosomal recessive disorder caused by mutations in the UDP-glucuronosyltransferase 1 isotype A1 (UGT1A1) gene and associated with toxic accumulation of unconjugated bilirubin in serum, we designed several UGT1A1 transgene expression cassettes and we packaged them into serotype 8 AAV vectors.We first performed the codon optimization of the UGT1A1 wildtype (w.t.) cDNA following two algorithms (v1 and v2), which led to cDNAs with nucleotide sequences significantly different from each other (nucleotide sequence homology of 77.5% for v1 and 78.3% for v2 vs. w.t.). Surprisingly, the sequence with a codon adaptation index closer to that of w.t. (w.t.=0.76, v1=0.76, v2=0.96) thus predicted to be the least efficient in terms of expression, showed the best performance in vitro in human hepatocyte cell lines, both at the RNA and protein levels. These results were confirmed in vivo in Ugt1a1-/- mice, a model of CN syndrome, where gene transfer with the optimized UGT1A1 resulted in better reduction of total bilirubin in serum. Next, we analyzed the 5’ untranslated region (UTR) of the expression cassette for sequences that may affect the efficacy of the transgene expression levels. Aside from the introduction of an optimized Kozak consensus sequence, the human beta2-globin (hBB2) intron sequence associated with the promoter revealed the presence of out of frame and in frame ATG codons before the start site of the UGT1A1 transgene. Removal of these cryptic ATGs from the intron sequence enhanced transgene expression, which resulted in stable, long-term correction of the disease phenotype following in vivo gene transfer. This demonstrated that the intron sequence optimization increases mRNA and protein levels in vitro and enhance the efficacy of the vector in vivo. Similar analysis was conducted in other common promoter/intron combinations used in AAV vector gene transfer.In conclusion, our results provide evidence that the combination of a potent liver specific promoter, codon optimization, and optimized untranslated region elements allow for decreasing the therapeutic dose of AAV vectors.

Safety and therapeutic efficacy of the switch to maraviroc+darunavir/ritonavir in HIV/HCV coinfected patients: initial results from GUSTA study.

IntroductionHIV/HCV coinfection is a risk factor for hepatic injury in patients receiving HAART and previous studies support a favourable effect of antiretroviral regimens including maraviroc (MVC) on the course of coinfection compared with other antiretroviral drugs. There are few observations about MVC use in simplified treatment of coinfected patients.Objective: To evaluate the efficacy and the safety of simplification to darunavir (DRV)/ritonavir (r)/maraviroc (MVC) in virologically HIV-suppressed patients and to explore the effect of simplified treatment on coinfected patients.Material and MethodsGUSTA study is a randomized two arms trial that compares the switch to DRV/r/MVC with standard HAART with three drugs. The study enrols patients with HIV-1 RNA<50cp/mL>6 months, R5 tropism, CD4>200 cells/mm. Survival analysis was used to analyze factors associated to time-to a single viral load (VL) over 50cp/mL and FIB-4>1.45.ResultsWe included 62 patients with at least the 24 week follow-up for FIB-4 analysis: males 75.8%, heterosexuals 48.4%, HCV+12.9% median age 48.3 years (IQR41.1;53.5), time from HIV diagnosis 11.0 years (IQR7.3;16.7), CD4 cells 659/mm (IQR478;882), nadir CD4 203/mm (IQR115;286), FPR 46 (IQR30;70), baseline (BL) FIB-4 1.11 (IQR0.75;1.35). At BL no differences were observed in the two arms, except for platelets (−34.96 109/L, in the study arm, p=0.028) and CD4 at nadir (−70cell/µL, p0.051). After 24 weeks a significant reduction in total bilirubin (TB) (−0.55 mg/dL, p=0.025) and alkaline phosphatase(AP) (−12.96 UI/L, p=0.002) was observed in the study group. A statistically significant difference in mean change of TB (0.61 mg/dL, p=0.016) and AP (13.23 UI/L, p=0.04) at 24 week between control and study group was observed. No grade 3/4 transaminase elevation was observed for any patient even if HIV/HCV coinfected and receiving MVC. A single HCV negative patient in the control arm had grade 3 bilirubin increase. Including all patients with at least one follow-up HCV status was not associated with an increased risk of detectable VL (n=114, 4072 person-week-follow-up [IQR12;51.6]), nor with FIB-4>1.45 (n=98, 3513 person-week-follow-up [IQR11.4;50.9]).ConclusionsThe initial results from GUSTA study show that ART-regimen including MVC did not increase the incidence of adverse events or severe laboratory liver abnormalities in HIV-1-infected patients with or without HCV coinfection. Coinfected patients did not show an increased risk of failure on simplification treatment with MVC/DRV/r.

Biliary Drainage in Patients With Unresectable, Malignant Obstruction Where ERCP Fails

Endoscopic retrograde cholangiopancreatography may fail because of malignant involvement of the second portion of the duodenum and the major papilla. Alternatives include percutaneous transhepatic biliary drainage (PTBD) or surgical bypass. Endoscopic ultrasonography-guided choledochoduodenostomy (EUS-CD) has been reported as an alternative. To prospectively compare EUS-CD and PTBD in patients with unresectable malignant biliary obstruction. Prospective and randomized study. Tertiary center. Success and efficacy comparison EUS-CD with PTBD. Twenty-five subjects were randomized (13 EUS-CD and 12 PTBD). Mean age was 67 years (SD, 11.9). The 2 groups were similar before intervention in terms of quality of life [EUS-CD (58.3) vs. PTBD (57.8); P=0.78], total bilirubin (16.4 vs. 17.2; P=0.7), alkaline phosphatase (539 vs. 518; P=0.7), and gamma-glutamyl transferase (554.3 vs. 743.5; P=0.56). All procedures were technically and clinically successful in both groups. At 7-day follow-up there was a significant reduction in total bilirubin in both the groups (EUS-CD, 16.4 to 3.3; P=0.002 and PTBD, 17.2 to 3.8; P=0.01), although no difference was noted comparing the 2 groups (EUS-CD to PTBD; 3.3 vs. 3.8; P=0.2). There was no difference between the complication rates in the 2 groups (P=0.44), EUS-CD (2/13; 15.3%) and PTBD (3/12; 25%). Costs were similar in the 2 groups also ($5673-EUS-CD vs. $7570-PTBD; P=0.39). Small sample size and single center study. EUS-CD can be an effective and safe alternative to PTBD with similar success, complication rate, cost, and quality of life.

Safety and Efficacy of Endoscopic Radiofrequency Ablation in Non-Resectable Cholangiocarcinoma: A Case Series

Purpose: Surgery remains the only curative treatment for cholangiocarcinomas. Less than 20% of tumors are resectable at the time of diagnosis. Median survival without surgery is about 3 months. Multiple studies have shown that photodynamic therapy plus biliary stenting improve jaundice, prolong survival and enhance quality of life. Endoscopic radiofrequency ablation (RFA) followed by self-expandable metal stenting has been shown to be safe and effective in small trials. Methods: Three patients with non-resectable hilar cholangiocarcinoma underwent ERCP and focal ablation therapy using an endoscopic bipolar radiofrequency probe, ENDOHPB (EMcizion Ltd, UK) at either 7 or 10 W for 90 seconds. Following the RFA, two patients had a non-covered self-expandable metal stent placed and the third had two bilateral plastic stents. All had a repeat ERCP following treatment. Results: Mean age was 68; two were females. There were no procedure-related complications. There was a significant reduction in total bilirubin (Table 1). At a mean of 89 days after initial treatment patients had repeat ERCP. Because of severe stricture, patient #3 received 10 W rather than 7 W at initial treatment and bilateral plastic stents were placed after ablation, in anticipation of possible retreatment at follow-up. At the time of repeat ERCP, the cholangiogram showed marked improvement of the malignant stricture diameter from <3 mm to 6 mm. A 12 mm extraction balloon was pulled through the stricture with minimal resistance. Further ablation was therefore withheld. Plastic stents were then replaced by an uncovered metal stent.Table: No Caption available.Conclusion: Endobiliary RFA is safe, well tolerated and may prove to be an effective palliative intervention that helps maintain biliary patency in patients with unresectable cholangiocarcinoma. It is possible that 10 W for 90 seconds may be as safe but more effective compared 7 W treatments for the same duration. Large randomized studies are needed to evaluate the safety and efficacy of this intervention.