Changes In Total Bilirubin Research Articles

Relationship between elevated bilirubin levels and enhanced warfarin effects during biliary obstruction.

A marked prolongation of the prothrombin time-international normalized ratio (PT-INR) is frequently observed during biliary obstruction in patients using warfarin. The objective of this study was to identify factors associated with PT-INR prolongation during biliary obstruction in patients using warfarin. Among 44 patients using warfarin who had biliary obstruction, we retrospectively investigated warfarin doses and laboratory data before and during biliary obstruction. The primary outcome was the association between changes in PT-INR (ΔPT-INR) and changes in laboratory data before and during biliary obstruction. Median PT-INR was 1.59 (IQR 1.38-1.95) before biliary obstruction and 2.27 (IQR 1.60-3.49) during biliary obstruction, indicating significant prolongation during the obstruction (P < 0.001). ΔPT-INR showed strong positive correlations with change in total bilirubin (ΔT-Bil; ρ = 0.692, P < 0.001) and change in conjugated bilirubin (ΔC-Bil; ρ = 0.731, P < 0.001). ΔPT-INR showed a weak negative correlation with the change in albumin (ΔAlb; ρ = -0.371, P < 0.05). When ΔPT-INR was used as the dependent variable in multiple linear regression analysis, ΔT-Bil, ΔC-Bil, and ΔAlb were significantly associated with ΔPT-INR. PT-INR was prolonged during biliary obstruction in patients using warfarin, and changes in bilirubin levels were associated with ΔPT-INR. If biliary obstruction with markedly elevated bilirubin levels occurs, measuring PT-INR could lead to safer warfarin therapy.

Reply: Insurance should cover vancomycin for primary sclerosing cholangitis.

Ali and colleagues raise issues of insurance coverage for oral vancomycin (OV) for the treatment of primary sclerosing cholangitis (PSC); however, the purpose of AASLD guidance statements is to help clinicians understand and implement the most recent evidence (https://www.aasld.org/practice-guidelines). The writing group, Practice Guidance Committee, and AASLD Governing Board and supported the final statement that there is insufficient evidence to recommend the use of OV which is consistent with the 2022 European Association for the Study of the Liver guidelines.1 The meta-analysis referred to included only 2 randomized controlled trials of OV.2. The largest study randomized 29 patients to OV or placebo for 12 weeks and reported an improvement in Mayo Risk Score, though total bilirubin did not change. The other randomized controlled trials was not placebo-controlled and included 8 and 9 patients who received low or high doses of OV, respectively, for 12 weeks. Compared with baseline, alkaline phosphatase decreased in both groups, and Mayo Risk Score decreased only in the low-dose group, but without change in total bilirubin. A third study was open-labeled and reported on 30 enrolled subjects and 29 patients treated outside protocol, 25 (42%) of whom had small duct PSC, and several previously treated with OV.3 The methods used to support the claims of imprvements in histology and cholangiograms were not reported. In contrast, a retrospective study of 264 patients found that neither OV nor ursodiol were associated with clinical improvements compared with observation in pediatric patients with PSC.4 Thus, the data supporting the use of OV in PSC is not “robust” and the statements Ali an colleagues made about OV are not supported by current evidence. More concerning is the suggestion that OV might be a substitute for biologics for treating inflammatory bowel disease. Management of PSC-associated inflammatory bowel disease was outside the scope of the Guidance, but multiple society guidelines do not recommend vancomycin for acute severe ulcerative colitis. All stakeholders desire a safe and effective treatment for PSC. Ali and colleagues believe that OV is that treatment, but current evidence does not support this belief.

Abstract 11274: VERVE-101—An Investigational Single-Course Gene Editing Medicine Targeting PCSK9—Durably and Potently Lowers PCSK9 and LDL-C Concentrations in Non-Human Primates

Introduction: VERVE-101 is an in vivo CRISPR base editing therapy designed to alter a single DNA base in the PCSK9 gene, permanently inactivate hepatic expression, and thereby durably lower LDL cholesterol (LDL-C). Here, we test the efficacy, tolerability, and potential for germline editing of VERVE-101 in studies of 43 non-human primates. Methods: Cynomolgus monkeys were dosed with a single intravenous infusion of a vehicle control (N = 10) or VERVE-101 at a dose of 0.75 mg/kg (N = 4) or 1.5 mg/kg (N = 22) with subsequent assessment of liver PCSK9 editing, reductions in blood PCSK9 and LDL-C, and safety parameters. A second study evaluated sexually mature male non-human primates dosed with a vehicle control (N = 1) or 1.5 mg/kg of VERVE-101 (N=6) to assess for any germline cell editing. Results: Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg respectively. This translated into reductions in blood PCSK9 of 69% and 89% and reductions of LDL-C of 50% and 68% at the 0.75 and 1.5 mg/kg doses, respectively, measured one year after dosing ( Figure). Liver safety monitoring noted a transient rise in ALT and AST concentrations following infusion that fully resolved by day 14 with no accompanying change in total bilirubin. VERVE-101 did not impact glucose homeostasis, as assessed by serial monitoring of fasting glucose and hemoglobin A1c. In the study to assess germline editing, VERVE-101 was similarly well tolerated and no editing of PCSK9 was observed in sperm samples obtained 90 days after dosing. Conclusions: A single intravenous infusion of VERVE-101 in non-human primates was well-tolerated and led to 89% lower blood PCSK9 protein and 68% lower blood LDL-C at one year after dosing. These results support initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease, with initial patient dosing anticipated in mid-2022.

Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models.

VERVE-101 is an investigational in vivo CRISPR base-editing medicine designed to alter a single DNA base in the PCSK9 gene, permanently turn off hepatic protein production, and thereby durably lower low-density lipoprotein cholesterol. We test the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of nonhuman primates and a murine F1 progeny study. Cynomolgus monkeys were given a single intravenous infusion of a vehicle control (n=10) or VERVE-101 at a dose of 0.75 mg/kg (n=4) or 1.5 mg/kg (n=22) with subsequent follow-up up to 476 days. Two studies assessed the potential for germline editing, including sequencing sperm samples from sexually mature male nonhuman primates treated with VERVE-101 and genotyping offspring from female mice treated with the murine surrogate of VERVE-101 (VERVE-101mu). Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg, respectively. This translated into mean reductions in blood PCSK9 (proprotein convertase subtilisin/kexin type 9) of 67% and 83% and reductions of low-density lipoprotein cholesterol of 49% and 69% at the 0.75 and 1.5 mg/kg doses, respectively, assessed as time-weighted average change from baseline between day 28 and up to 476 days after dosing. Liver safety monitoring noted a transient rise in alanine aminotransferase and aspartate aminotransferase concentrations after infusion that fully resolved by day 14 with no accompanying change in total bilirubin. In a subset of monkeys necropsied 1 year after dosing, no findings related to VERVE-101 were identified on macroscopic and histopathologic assessment of the liver and other organs. In the study to assess potential germline editing of male nonhuman primates, sperm samples collected after VERVE-101 dosing showed no evidence of PCSK9 editing. Among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the PCSK9 edit was transmitted in 0 of 436 animals. VERVE-101 was well tolerated in nonhuman primates and led to 83% lower blood PCSK9 protein and 69% lower low-density lipoprotein cholesterol with durable effects up to 476 days after dosing. These results have supported the initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease.

Effect of Common Chicory Essence and Phototherapy on Serum Bilirubin Levels in Preterm Infants Admitted to Neonatal Intensive Care Unit: An In Vitro Study

: Jaundice is a common neonatal disorder that occurs in most term and preterm infants. Chicory or dandelion flower has long been used in the treatment of jaundice. This study aimed to investigate the effect of common chicory essence and phototherapy on serum bilirubin levels in preterm infants admitted to the neonatal intensive care unit (NICU) of Valiasr Hospital in Birjand, Iran. This in vitro study was conducted on preterm infants with gestational age of less than 37 weeks and weight less than 2500 g. Bilirubin levels in blood samples from 21 infants were measured before and after the addition of chicory essence or distilled water. Then, phototherapy was performed, and bilirubin levels were measured again. Data were analyzed using SPSS (version 21). The mean weight of infants was 1542.8 ± 453.5 g. In the chicory essence group, the mean total serum bilirubin was 5.29 ± 1.55 and 0.18 ± 0.07 mg/dL before and after the intervention, respectively (P &lt; 0.001). The mean indirect serum bilirubin was 4.96 ± 1.59 and 0.18 ± 0.07 mg/dL before and after the intervention, respectively (P &lt; 0.001). The mean changes in total bilirubin in the distilled water and chicory groups were 5.15 ± 1.70 and 5.43 ± 1.99 mg/dL, respectively (P = 0.62). The results showed that both distilled water and chicory essence decreased direct and total serum bilirubin concentrations. The indirect bilirubin changes were not significant, and there was no difference in the total bilirubin changes between the two groups. Totally, the chicory essence had no effect on reducing the serum bilirubin level in preterm infants.

Learning Curve Analysis of Microvascular Hepatic Artery Anastomosis for Pediatric Living Donor Liver Transplantation: Initial Experience at A Single Institution.

BackgroundThe incidence of hepatic artery thrombosis in pediatric living donor liver transplantation (LDLT) is significantly higher than that in adults, and is closely related to the surgeon’s experience with hepatic artery anastomosis. However, there are few studies on the learning curve of hepatic artery anastomosis among surgeons.MethodsWe collected data related to 75 patients who underwent pediatric LDLT and hepatic artery anastomosis independently by the same surgeon. Cumulative sum method (CUSUM) was used to analyse the duration of hepatic artery anastomosis and determine the cut-off value. Patients were divided into two phases according to CUSUM. We analysed the intraoperative and postoperative data and survival outcomes of the included patients.ResultsTotal anastomosis duration decreased with an increased number of completed procedures, and the average duration was 42.4 ± 2.20 min. A cut-off value and two phases were identified: 1–43 cases and 44–75 cases. Intraoperative blood loss was significantly lower in phase 2 than in phase 1. The immediate functional changes of total bilirubin (TBIL) and direct bilirubin (DBIL) were significantly also lower in phase 2 than in phase 1. Other functional outcomes, postoperative complications, and the long-term survival rate were not significantly different between the two phases.ConclusionsTechnical competence in pediatric LDLT hepatic artery anastomosis may be achieved after completing 43 cases. It is a safe procedure with a surgical loupe that can be systematized and adopted by pediatric surgeons with sufficient experience via a relatively long learning curve.

Clinical efficacy and safety of lymphocyte apheresis combined with plasma exchange in the treatment of patients with hepatitis B virus-related liver failure at the ascending stage

To analyze and summarize the clinical efficacy and safety of lymphocyte apheresis combined with plasma exchange in the treatment of patients with hepatitis B virus-related liver failure at the ascending stage. A observational study was conducted. A total of 69 hepatitis B virus-related liver failure at the ascending stage patients who were hospitalized at Affiliated Guangzhou Eighth People's Hospital of Guangzhou Medical University from January 2016 to December 2020 were enrolled in this study. The patients were grouped according to their condition and wishes, including 38 patients treated with conservative medical treatment (control group) and 31 patients treated with lymphocyte apheresis combined with plasma exchange based on comprehensive medical treatment (study group). Clinical data were compared between the two groups 1-4 weeks after treatment, including dynamic changes of total bilirubin (TBil), international normalized ratio (INR), alanine aminotransferase (ALT), model for end-stage liver disease (MELD) score, and the rate of clinical improvement at 4 weeks after treatment. In addition, the adverse effects and dynamic changes of white blood cell count (WBC), lymphocyte count (LYM), platelet count (PLT), and hemoglobin (Hb) within 4 weeks after treatment were compared between the two groups. Both groups showed significant improvement in clinical parameters after 1-4 weeks of initiation of therapy. The improvement of TBil, INR and MELD score at 1-4 weeks after treatment were significantly better in the treatment group than those in the control group [TBil (μmol/L): 248 (117, 335) vs. 398 (328, 464) at 1 week, 173 (116, 278) vs. 326 (184, 476) at 2 weeks, 107 (84, 235) vs. 355 (129, 467) at 3 weeks, 70 (61, 172) vs. 290 (82, 534) at 4 weeks; INR: 1.72±0.70 vs. 2.13±0.69 at 1 week, 1.67±0.61 vs. 2.28±1.35 at 2 weeks, 1.65±0.75 vs. 2.15±0.92 at 3 weeks, 1.61±0.93 vs. 2.19±1.17 at 4 weeks; MELD score: 18.35±5.32 vs. 23.38±4.56 at 1 week, 16.47±5.16 vs. 23.71±7.94 at 2 weeks, 16.30±5.75 vs. 22.64±6.99 at 3 weeks, 14.63±6.76 vs. 20.97±8.19 at 4 weeks], with significant differences (all P < 0.05). In addition, ALT levels at 1 week and 2 weeks after treatment in the study group were significantly lower than those in the control group [U/L: 128 (93, 206) vs. 240 (167, 436) at 1 week, 64 (42, 110) vs. 85 (69, 143) at 2 weeks, both P < 0.05]. The rate of clinical improvement at 4 weeks after treatment in the study group was 54.84% (17/31), which was significantly higher than that in the control group [28.95% (11/38)], with statistically significant difference (P < 0.05). There was no significant difference in the rate of new infection between the study group and the control group [22.58% (7/31) vs. 34.21% (13/38), P > 0.05]. Additionally, expect that the PLT level at 1 week after treatment in the study group was significantly lower than that in the control group (×109/L: 101±42 vs. 128±59, P < 0.01), there was no significant difference in WBC, LYM or Hb at different time points after treatment between the two groups. Clinical efficacy of lymphocyte apheresis combined with plasma exchange based on comprehensive medical treatment in the treatment of patients with hepatitis B virus-related liver failure at the ascending stage is superior to conservative medical treatment alone, which can improve clinical improvement rate and recovery rate of liver function with high safety.

Long-Term Outcomes After Percutaneous Transluminal Pulmonary Angioplasty in Patients With Takayasu Arteritis and Pulmonary Hypertension.

ObjectiveTo investigate the long-term efficacy of percutaneous transluminal pulmonary angioplasty (PTPA) in patients with Takayasu arteritis (TA) and pulmonary artery stenosis and pulmonary hypertension (PH).MethodsData from 183 lesions from 79 surgeries performed on 32 patients with TA and PH were analyzed. Symptoms, laboratory investigation results, World Health Organization (WHO) functional class, 6-min walk distance (6 MWD), hemodynamic parameters, and prognosis were analyzed at baseline and follow-up.ResultsThe mean (± SD) age of the 32 patients (28 female, 4 male) was 42.8 ± 11.9 years, and the median follow-up was 49.5 months (interquartile range, 26–71 months). Compared with baseline, changes in total bilirubin, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, 6 MWD, and WHO score functional class demonstrated significant differences (P<0.001). Echocardiography findings, right and left ventricular diameter, tricuspid annular plane systolic excursion, and estimated pulmonary artery systolic pressure were all improved (P=0.016, P<0.001, P<0.001, and P=0.005, respectively). Importantly, repeat right heart catheterization revealed that mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac index also improved significantly at follow-up (P<0.001, P<0.001, and P=0.011, respectively). Pulmonary angiography revealed post-procedure restenosis in 64 (35.0%) lesions underwent PTPA within three to six months. Among three patients who underwent stent implantation, one experienced restenosis. Two patients died during the follow-up period, one from aggravation of right heart failure after lung infection, and the other in a traffic accident.ConclusionsResults of this study indicated that PTPA significantly improved clinical symptoms, exercise tolerance, and hemodynamic parameters in patients with TA pulmonary artery stenosis and PH. More importantly, reperfusion pulmonary edema significantly decreased, and no patient died of PTPA-related complications with guidance from the pressure wire.

Standard volume plasma exchange is safe and effective for patients with acute liver failure.

Background and Aim: Plasma exchange (PLEX) is an effective bridging therapy for patients with acute liver failure(ALF). There are no studies comparing the efficacy of standard volume (SV) vs. high volume (HV) PLEX. Therefore, we aimed to compare the safety and efficacy of SV PLEX with HV PLEX. Methods: Patients with ALF who underwent PLEX were included in this retrospective study. The primary outcome was to compare the transplant-free survival among SV (total plasma volume x 1) and HV (total plasma volume x 1.5) PLEX groups at 30-days. Secondary objectives were to compare the effect of SV and HV PLEX on total bilirubin, INR, ammonia levels, SOFA, and MELD Na scores, and the adverse events related to PLEX. Results: A total of 17 patients underwent PLEX(SV-8 and HV-9).The mean age and severity scores (SOFA-4.13 ±1.72 in SV group vs. 4.89±1.7 in HV group; P=0.37) were similar among both the groups. Most common cause of ALF was viral in each group. Fifty percent in SV and 34% in HV group satisfied King’s College Criteria for liver transplantation(P=0.41). Each patient in both the groups underwent a median of 2 sessions of PLEX. Post-PLEX, the change in total bilirubin, INR, ammonia, SOFA, and MELD Na score was comparable. Mortality at seven days was similar among both groups (SV-12.5% vs. 33.3% in HV; P=0.57). Mortality at day 30 was 25% in SV compared to 67% in the HV group (P=0.1). On Kaplan Meier analysis, transplant-free survival at day 30 was similar in both the groups (P=0.26). Two patients in the HV group developed volume overload features and were managed conservatively compared to none in the single volume group. Conclusions: Standard volume plasma exchange has similar efficacy as high volume plasma exchange on severity scores. Standard volume plasma exchange is safe and effective for patients with acute liver failure.

Post-transfusion hemoglobin response in patients with cirrhosis: Can we expect a 1 g/dL rise per unit transfused?

A patient's hemoglobin is typically expected to rise by 1 g/dL/unit transfused PRBCs. However, it has been theorized that mechanisms such as hyperbilirubinemia and splenomegaly might lead to either a direct lysis or sequestration of red blood cells that could decrease this proportionate response. Patients with resolved GI bleeding but still requiring transfusion to correct anemia were compared in cirrhosis and control groups. A retrospective chart review between 2015 and 2020 was conducted at a single institution. Data collected included age, sex, BMI, GI bleed diagnosis, number of PRBCs transfused, presence of splenomegaly and spleen size, alcohol use history, type of cirrhosis, MELD-Na at admission, GFR, and pre-and post-transfusion labs: total bilirubin, ALT, hemoglobin, hematocrit. A logic regression was performed for each group looking at which factors were associated with a successful response (defined as >0.9 g/dL hemoglobin per unit transfused). Mean change in hemoglobin was 0.77 g/dL in patients with cirrhosis compared to 1.46 g/dL in patients without (P < .001, N = 103). Odds ratios for presence of splenomegaly (0.22, N = 78) and female sex (4.39, N = 102) in predicting adequate response (>0.9 g/dL/unit) were both significant (P = .002) as well as portal hypertensive bleed diagnosis (0.28, N = 85, P = .0015). Factors that did not contribute included: age, race, BMI, alcohol use, GFR, change in ALT, and change in total bilirubin. Patients with cirrhosis have an approximately 50% decreased response to transfusion with PRBCs after resolution of a gastrointestinal bleed in comparison to patients without cirrhosis. Risk factors included splenomegaly, portal hypertension, and male sex.

Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir

BackgroundCabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.ObjectivesTo investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks).MethodsPlasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809).ResultsStatistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%–50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%–24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10−5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT.ConclusionsThis modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.

Association of disease condition with changes in intestinal flora, and plasma endotoxin and vascular endothelial growth factor levels in patients with liver cancer.

Currently, the therapeutic effect on patients with liver cancer is associated with disease development. Meanwhile, the efficacy in patients with advanced liver cancer is far from satisfactory. Therefore, the aim of this study was to explore the association of disease condition with changes in liver function indexes, intestinal flora, and plasma endotoxin (ET) and vascular endothelial growth factor (VEGF) levels in patients with liver cancer. A total of 300 patients with primary liver cancer in our hospital were enrolled in this study. All patients were divided into three groups, including early liver cancer group, middle liver cancer group, and advanced liver cancer group. Peripheral blood was collected from each subject to detect liver function indexes, procalcitonin (PCT), plasma ET, and VEGF levels. Furthermore, mid-posterior-segment stools were collected from 15 cases in each group, and sent to the company for detection of intestinal flora. Liver function indexes in peripheral blood of patients with liver cancer changed with the changes in disease condition. With the progression of liver cancer, the level of aspartate aminotransferase (AST) increased significantly, and the highest was observed in advanced liver cancer patients [(91.18±10.34) U/L] (p=0.046). However, the level of plasma total protein declined significantly, which was (24.83±1.75) g/L in advanced liver cancer patients (p=0.035). The changes in total bilirubin were significantly associated with the progression of liver cancer (p=0.003). The abundance of Clostridiales, Firmicutes, and Streptococcus in the intestinal tract was high in early liver cancer group. The abundance of Ruminococcaceae, Pasteurellaceae, Tanticharoenia, and Vagococcus in the intestinal tract was high in middle liver cancer group. Meanwhile, the abundance of Bifidobacteriales, Actinobacteria, Barnesiella, Porphyromonadaceae, and Pseudomonadales in the intestinal tract was high in advanced liver cancer group. In patients with liver cancer, the level of Enterobacteriaceae was positively correlated with that of Firmicutes (r=0.36, p=0.003), whereas it was negatively correlated with Lactobacillus (r=-0.72, p=0.021). The level of Lactobacillus was positively correlated with that of Ruminococcaceae (r=0.39, p=0.043), whereas it was negatively correlated with that of Firmicutes (r=-0.27, p=0.019). In addition, the level of PCT markedly rose in advanced liver cancer group [(6.89±0.35) ng/mL] (p=0.021). The level of ET increased significantly with the development of liver cancer, with the highest level observed in advanced liver cancer group [(0.71±0.09) EU/mL] (p=0.004). The level of VEGF also increased remarkably with the aggravation of liver cancer, and the highest was found in advanced liver cancer group [(112.33±2.11) μmol/L], showing differences among groups (p<0.05). With the progression of liver cancer, the abundance of Barnesiella, etc., rose and that of Ruminococcaceae, etc., declined in the intestinal tract. Meanwhile, the composition of intestinal flora was changed, and the levels of plasma ET and VEGF increased.

Association Between the Change in Total Bilirubin and Risk of Bleeding Among Patients With Nonvalvular Atrial Fibrillation Taking Dabigatran.

There is still a lack of effective biomarkers for the prediction of the risk of bleeding events among patients with nonvalvular atrial fibrillation (NVAF) taking dabigatran. This study aimed to investigate the association between change in total bilirubin (CTBIL) and risk of bleeding among patients with NVAF taking dabigatran. The CTBIL was the difference in serum total bilirubin at out of follow-up from baseline serum total bilirubin. A total of 486 patients with NVAF treated with dabigatran (110 mg twice daily) were recruited from 12 centers in China from February 2015 to December 2017. All patients were followed for 3 months. Cox proportional hazards regression analysis was used to evaluate the association between the CTBIL and bleeding. Moreover, a Cox proportional hazards regression with cubic spline functions and smooth curve fitting (the penalized spline method) and 2 piecewise Cox proportional hazards models were used to address the nonlinearity between CTBIL and bleeding. The mean (SD) follow-up duration was 81.2 (20.2) days. In all, 67 patients experienced bleeding events. A U-shaped association was observed between the CTBIL and bleeding, with increased hazard ratios (HRs) in relation to either low or high CTBIL levels. For CTBIL <6.63 µmol/L, the HR (95% confidence interval [CI]) was 0.90 (0.84-0.96), and for CTBIL ≥6.63 µmol/L, the HR (95% CI) was 1.35 (1.14-1.60). Our findings showed a U-shaped relationship between CTBIL and bleeding. Both low and high levels of CTBIL were associated with a higher risk of bleeding.

Intravenous Versus Oral Iron Replacement in Patients with a Continuous-Flow Left Ventricular Assist Device.

Intravenous Versus Oral Iron Replacement in Patients with a Continuous-Flow Left Ventricular Assist Device.

2360 Progression of Post-Islet Cell Transplantation Hepatic Steatosis to Cirrhosis: A Rare Complication of a Common Finding

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a growing cause of liver disease in the USA and throughout the rest of the world and is predicted to soon become the leading indication for liver transplantation. NAFLD exists on a spectrum from hepatic steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis. It is closely related to metabolic syndrome and insulin resistance. A lesser known cause of hepatic steatosis is islet cell allotransplantation and autotransplantation, which are experimental treatments for Type 1 Diabetes Mellitus and FDA- approved treatment for patients with chronic pancreatitis who have undergone pancreatectomy, respectively. In this case, we present the first case of post-islet cell transplantation hepatic steatosis progressing to cirrhosis. CASE DESCRIPTION/METHODS: The patient is a 27 year old female with a history of chronic pancreatitis secondary to cystic fibrosis, status-post total pancreatectomy and islet cell autotransplantation, complicated by development of non-alcoholic steatohepatitis. Her NASH was treated with probiotics and vitamin E supplementation. Eight years after her islet cell transplant, she was hospitalized for nausea, vomiting, and abdominal pain. A CT scan showed that she had developed severe, diffuse hepatic steatosis. Her ALP and AST were mildly elevated. ALT and total bilirubin were normal. She had facial and pedal edema, but no other stigmata of cirrhosis. She underwent a liver biopsy which showed bridging fibrosis and a small regenerative nodule with steatohepatitis. It was with these findings that she was diagnosed with cirrhosis. DISCUSSION: Hepatic steatosis has been reported with a prevalence of 20-40% of patients following islet cell transplantation. These reports have not been associated with any long term liver or graft survival outcomes. The usual onset of histological findings in one study was approximately 3 years after transplant, and some of these cases resolved over time. These reported cases did not have any changes in total bilirubin, ALP, AST, or ALT. Hepatic steatosis from islet transplantation is thought to develop due to the paracrine effect of localized hyperinsulinemia and fatty acid infiltration from the islet cells, which are inserted into the portal vein and taken to the liver during transplant. To our knowledge, this is the only reported case in which post-islet cell transplantation hepatic steatosis progressed to NASH cirrhosis along with abnormal liver biomarkers.

Drug-Induced Autoimmune Hepatitis in a Patient Treated With Minocycline: A Rare Adverse Effect

Minocycline is an oral broad-spectrum tetracycline antibiotic that is used to treat moderate to severe acne vulgaris as well as certain sexually transmitted infections. Minocycline-induced autoimmune hepatitis can be differentiated from “classic” autoimmune hepatitis by the patient's swift recovery after discontinuing the offending drug and no relapse of the condition upon discontinuation of treatment with corticosteroids. A 31-year-old Chinese woman, with past medical history of acne vulgaris, presented to the Emergency Department with nausea, vomiting, and abdominal pain for the last 3-4 days. She had experienced three episodes of non-bloody, non-bilious vomiting. She described a persistent dull aching pain in the right upper quadrant of the abdomen that had been increasing in intensity, particularly over the last two days. She denied any recent change in her diet. She reported that no one in her household had experienced similar symptoms. She denied any additional recent symptoms. Upon medication reconciliation, it was discovered that the patient had been taking minocycline, on her own and not under medical supervision, for the past three months. Initial laboratory testing was remarkable for significantly elevated transaminase levels with aspartate aminotransferase (AST) of 718 U/L (10-35 U/L) and alanine aminotransferase (ALT) of 1138 U/L (10-55 U/L). An autoimmune workup revealed an elevated antinuclear antibody (ANA) titer (1:160) (<1:40), positive anti-smooth muscle antibodies (ASMA), and the finding of hypergammaglobulinemia (3.2 g/dL) (0.7-1.6 g/dL) with elevated levels of serum immunoglobulin G (IgG) (3176 mg/dL) (700-1600 mg/dL). The bilirubin levels decreased steadily from Day 1 of the hospital admission, but the transaminase levels continued to rise despite discontinuation of the minocycline (Figure 2). On Day 7, she was started on treatment with prednisolone. Also, an IR-guided liver biopsy was performed for the purpose of confirming the diagnosis as well as to assess the degree of liver injury (Figure 3). After two days of treatment with prednisolone, the patient's transaminase levels began to decrease steadily (Figure 2). Physicians should be informed about and suspect drug-induced hepatitis for any individual taking minocycline who presents with elevated LFTs. Physicians who prescribe it to treat acne vulgaris should be aware of this potentially severe adverse effect and stop it immediately when suspicion is raised.2316_B Figure 2. Changes in total bilirubin and alanine aminotransferase (ALT) before and after treatment with prednisolone *Prednisolone, at an initial dose of 50 mg/day, was started on Day 7 of the hospital admission.2316_C Figure 3. Figure 3 (A, B, C, D; left to right). Histopathologic images of the patient's drug-induced hepatitis from liver biopsy A) Piecemeal necrosis. There is chronic inflammation in the portal tracts. H&E stain. 100x. B) Again, there is chronic inflammation in the portal tracts with many plasma cells, lymphocytes, and occasional eosinophils. H&E stain. 400x. C) and D) Spotty necrosis. There is mild chronic inflammation in the portal tracts, as well as ballooning degeneration of hepatocytes indicative of hepatocellular injury. H&E stain. 100x and 400x, respectively.2316_A Figure 1. Abdominal ultrasound There is mild hepatomegaly with increased liver echogenicity.

Nutritional prognostic scores in patients with hilar cholangiocarcinoma treated by percutaneous transhepatic biliary stenting combined with 125I seed intracavitary irradiation: A retrospective observational study.

We mainly aimed to preliminarily explore the prognostic values of nutrition-based prognostic scores in patients with advanced hilar cholangiocarcinoma (HCCA).We retrospectively analyzed 73 cases of HCCA, who underwent percutaneous transhepatic biliary stenting (PTBS) combined with 125I seed intracavitary irradiation from November 2012 to April 2017 in our department. The postoperative changes of total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin (ALB) were observed. The preoperative clinical data were collected to calculate the nutrition-based scores, including controlling nutritional status (CONUT), C-reactive protein/albumin ratio (CAR), and prognostic nutritional index (PNI). Kaplan–Meier curve and Cox regression model were used for overall survival (OS) analyses.The serum levels of TBIL, DBIL, ALT, AST, and ALP significantly reduced, and ALB significantly increased at 1 month and 3 months postoperatively. The median survival time of the cohort was 12 months and the 1-year survival rate was 53.1%. Univariate analysis revealed that the statistically significant factors related to OS were CA19-9, TBIL, ALB, CONUT, and PNI. Multivariate analysis further identified CA19-9, CONUT, and PNI as independent prognostic factors.Nutrition-based prognostic scores, CONUT and PNI in particular, can be used as predictors of survival in unresectable HCCA.

Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation

The association of posaconazole serum concentrations and toxicity is unclear. An assessment of whether levels obtained with the delayed-release tablet (DRT) formulation are correlated with abnormal liver function test (LFT) results and/or QTc prolongation was undertaken. This was a multicentre, retrospective, observational study of adult patients with cancer between 26 November 2013 and 14 November 2014. Patients were included if they received posaconazole DRT with a posaconazole level obtained between days 5 and 14. Clinical data, including demographics, hepatotoxic medications, posaconazole levels, LFTs and QTc intervals, were obtained. Association of factors with changes in LFTs and QTc prolongation was assessed using linear and logistic regression. One hundred and sixty-six study patients were included. The median posaconazole level was 1250 (range 110-4220) ng/mL and the median time until level was 6 (range 5-14) days. There was a statistically significant increase in AST ( P < 0.001), ALT ( P < 0.001), alkaline phosphatase (ALK) ( P < 0.001), total bilirubin (TBILI) ( P < 0.001) and QTc ( P = 0.05) from baseline. Posaconazole levels were not associated with increases in AST [β (SE) = -0.33 (2.2), P = 0.88], log ALT [β (SE) = -0.02 (0.03), P = 0.63], ALK [β (SE) = 2.2 (2.9), P = 0.46] and TBILI [β (SE) = -0.01 (0.04), P = 0.88]. For each additional hepatotoxic medication, there was a mean change in TBILI of 0.13 mg/dL ( P = 0.02) and ALK of 7.1 U/L ( P = 0.09). No statistically significant association between posaconazole level and QTc interval prolongation was found. We did not identify an association between posaconazole serum concentrations and LFT elevations or QTc prolongation. However, some LFTs were found to increase with more hepatotoxic medications administered.

Hematological and serum biochemical studies in fresh water fish exposed to acute and chronic copper and mercury toxicity

A total number of 668 apparently healthy fish were obtained from farm to study the effect of two heavy metals in a form of (Copper sulfate and Mercuric chloride) on some hematological and biochemical parameters of blood. The LC 50 /96 hr. of Cu and Hg were estimated and fish exposed to ½ LC50 for 7 days and for 1/10 LC50 for 8 weeks from each product separately. Results showed decrease in RBCs count, PCV% and Hb in acute and chronic mercury while a significant increase was shown in acute and chronic copper toxicity, total leucocytic count showed decrease in acute mercury toxicity and increase in the chronic case, while in copper toxicity non-significant decrease in acute and significant decrease in chronic toxicity was noticed. Elevated serum urea and creatinine in both acute and chronic mercury and copper toxicity was detected. No changes in total bilirubin in the acute mercury and chronic copper toxicity while significant increase in chronic mercury and acute copper. Elevation of serum AST and ALT in some days of acute toxicity of mercury and copper while in chronic mercury toxicity a significant elevation of both serums AST and ALT were detected .while in chronic copper toxicity serum AST was fluctuated and ALT showed no significant changes. CK study revealed significant decrease in acute mercury with fluctuation in the chronic toxicity while in copper toxicity it showed fluctuation in acute and significant decrease in chronic toxicity. Glucose value decreased in acute and chronic mercury toxicity while in copper toxicity it showed significant increase in the acute and increase followed by significant decrease in the chronic copper toxicity.

Chronic exposure of adult, postnatal and in utero rat models to low-dose 137Cesium: impact on circulating biomarkers.

The presence of 137Cesium (137Cs) in the environment after nuclear accidents at Chernobyl and more recently Fukushima Daiichi raises many health issues for the surrounding populations chronically exposed through the food chain. To mimic different exposure situations, we set up a male rat model of exposure by chronic ingestion of a 137Cs concentration likely to be ingested daily by residents of contaminated areas (6500 Bq.l−1) and tested contaminations lasting 9 months for adult, neonatal and fetal rats. We tested plasma and serum biochemistry to identify disturbances in general indicators (lipids, proteins, carbohydrates and electrolytes) and in biomarkers of thyroid, heart, brain, bone, kidney, liver and testis functions. Analysis of the general indicators showed increased levels of cholesterol (+26%), HDL cholesterol (+31%), phospholipids B (+15%) and phosphorus (+100%) in the postnatal group only. Thyroid, heart, brain, bone and kidney functions showed no blood changes in any model. The liver function evaluation showed changes in total bilirubin (+67%) and alkaline phosphatase (–11%) levels, but only for the rats exposed to 137Cs intake in adulthood. Large changes in 17β-estradiol (–69%) and corticosterone (+36%) levels affected steroidogenesis, but only in the adult model. This study showed that response profiles differed according to age at exposure: lipid metabolism was most radiosensitive in the postnatal model, and steroid hormone metabolism was most radiosensitive in rats exposed in adulthood. There was no evidence of deleterious effects suggesting a potential impact on fertility or procreation.