Differences In Liver Function Research Articles

B-ultrasound-guided Intrahepatic Infusion of Autologous Bone Marrow Cells for Decompensated Cirrhosis

Objective: To study the therapeutic effect of B-ultrasound-guided intrahepatic infusion of autologous bone marrow nucleated cells on decompensated cirrhosis. Methods: To observe the clinical treatment of 75 cases of decompensated cirrhosis. Among them, 30 cases received routine liver protection and diuretic treatment. 45 cases were treated by percutaneous transhepatic infusion of autologous bone marrow nucleated cells under the guidance of B ultrasound. There were no significant differences in liver function and blood routine indexes between the two groups before treatment (p > 0.05). Results: The indexes of liver function and blood routine at different time periods of 1 month, 3 months, 6 months, and 12 months in the conventional treatment group did not change significantly. 6 cases died of liver failure within 1 year, the fatality rate was 20%. The indexes of liver function and blood routine of percutaneous liver transhepatic infusion of autologous bone marrow nucleated cells at 1 month, 3 months, 6 months, and 12 months under the guidance of B-ultrasound were significantly better than those of the conventional treatment group (p < 0.05). One case died of gastrointestinal bleeding in the group of percutaneous transhepatic infusion of autologous bone marrow nucleated cells guided by B ultrasound, with a fatality rate of 2.5%. Compared with the conventional treatment group, there were significant differences (p < 0.05). Conclusion: Conventional drug therapy has no obvious effect on decompensated cirrhosis. Intrahepatic infusion of bone marrow nucleated cells can significantly promote liver function reconstruction in decompensated cirrhosis.

Comparison of the therapeutic effects of three minimally invasive approaches for laparoscopic cholecystectomy combined with common bile duct exploration—— a 5-year retrospective analysis

ObjectiveThe aim of this retrospective study was to explore the indications for three minimally invasive approaches—T-tube external drainage, double J-tube internal drainage, and primary closure—in laparoscopic cholecystectomy combined with common bile duct exploration.MethodsThree hundred eighty-nine patients with common bile duct stones who were treated at the Second People's Hospital of Hefei between February 2018 and January 2023 were retrospectively included. Patients were divided into three groups based on the surgical approach used: the T-tube drainage group, the double J-tube internal drainage group, and the primary closure group. General data, including sex, age, and BMI, were compared among the three groups preoperatively. Surgical time, length of hospital stay, pain scores, and other aspects were compared among the three groups. Differences in liver function, inflammatory factors, and postoperative complications were also compared among the three groups.ResultsThere were no significant differences among the three groups in terms of sex, age, BMI, or other general data preoperatively (P > 0.05). There were significant differences between the primary closure group and the T-tube drainage group in terms of surgical time and pain scores (P < 0.05). The primary closure group and double J-tube drainage group differed from the T-tube drainage group in terms of length of hospital stay, hospitalization expenses, and time to passage of gas (P <0.05). Among the three groups, there were no statistically significant differences in inflammatory factors or liver function, TBIL, AST, ALP, ALT, GGT, CRP, or IL-6, before surgery or on the third day after surgery (P > 0.05). However, on the third day after surgery, liver function in all three groups was significantly lower than that before surgery (P<0.05). In all three groups, the levels of CRP and IL-6 were significantly lower than their preoperative levels. The primary closure group had significantly lower CRP and IL-6 levels than did the T-tube drainage group (P < 0.05). The primary closure group differed from the T-tube drainage group in terms of the incidences of bile leakage and electrolyte imbalance (P < 0.05). The double J-tube drainage group differed from the T-tube drainage group in terms of the tube dislodgement rate (P < 0.05).ConclusionAlthough primary closure of the bile ducts has clear advantages in terms of length of hospital stay and hospitalization expenses, it is associated with a higher incidence of postoperative complications, particularly bile leakage. T-tube drainage and double J-tube internal drainage also have their own advantages. The specific surgical approach should be selected based on the preoperative assessment, indications, and other factors to reduce the occurrence of postoperative complications.

Comparison of the effects of remimazolam tosylate and propofol on immune function and hemodynamics in patients undergoing laparoscopic partial hepatectomy: a randomized controlled trial

BackgroundLaparoscopic partial hepatectomy inevitably decrease patient immune function. Propofol has been shown to have immunomodulatory effects but is associated with hemodynamic side effects. Despite studies showing a negligible impact of remimazolam tosylate on hemodynamics, it has not been reported for partial hepatectomy patients. Its influence on immune function also remains unexplored. This study sought to investigate the differences in immune function and intraoperative hemodynamics between patients who underwent laparoscopic partial hepatectomy with remimazolam tosylate and those who underwent laparoscopic partial hepatectomy with propofol.MethodsThis was a single-center, randomized controlled trial involving 70 patients, who underwent elective laparoscopic partial hepatectomy. The patients were randomly divided into two groups: the remimazolam group (group R) and the propofol group (group P). In this study, the primary outcomes assessed included the patient’s immune function and hemodynamic parameters, and the secondary outcomes encompassed the patient’s liver function and adverse events.ResultsData from 64 patients (group R, n = 31; group P, n = 33) were analyzed. The differences in the percentages of CD3+, CD4+, CD8+, and NK cells and the CD4+/CD8+ ratio between the two groups were not statistically significant at 1 day or 3 days after surgery. Compared with those in group P, the MAP and HR at T2 and the MAP at T1 in group R were significantly increased(P < 0.05). The differences in HR and MAP at T0, T3, T4, T5, T6, and T7 and HR at T1 between the two groups were not statistically significant. There were no differences in liver function or adverse effects between the two groups, suggesting that remimazolam tosylate is a safe sedative drug(P > 0.05).ConclusionThe effects of remimazolam tosylate on the immune function of patients after partial hepatectomy are comparable to those of propofol. Additionally, its minimal effect on hemodynamics significantly decreases the incidence of hypotension during anesthesia induction, thereby enhancing overall perioperative safety.Trial registrationThe trial was registered on May 9, 2022 in the Chinese Clinical Trial Registry, registration number ChiCTR2200059715 (09/05/2022).

Associations between liver function and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in non-demented adults: The CABLE study.

Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (β = -0.115, pFDR < 0.001), GLO (β = -0.184, pFDR < 0.001), and A/G (β = 0.182, pFDR < 0.001) and CSF β-amyloid1-42 (Aβ1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.

Systematic Analysis of the Mechanism of Polygoni Multiflori Caulis in Improving Depressive Disorder in Mice via Network Pharmacology Combined with Ultra-High Performance Liquid Chromatography Coupled with Quadrupole Exactive Orbitrap Mass Spectrometer.

Depressive disorder (DD) is a common chronic and highly disabling disease. Polygoni Multiflori Caulis (PMC), a traditional Chinese medicine, has been listed in the 2020 edition of the Chinese Pharmacopoeia. Here, the antidepressant effects and mechanisms of PMC were explored for the first time. We observed the safety of PMC at a 10-fold clinically equivalent dose. Depressed mice were induced by chronic unpredictable mild stress (CUMS) and were used to evaluate the antidepressant effects of PMC via the sucrose preference test and the tail suspension test. The composition of PMC was identified by ultra-high performance liquid chromatography coupled with quadrupole exactive orbitrap mass spectrometer, and the active components, important targets, and potential mechanism of PMC in DD treatment were predicted via network pharmacology. Investigation included active compounds and DD-related targets screening, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation, PMC-compound-target-pathway- DD network construction, and Molecular docking. In the safety evaluation of PMC, no toxic side effects or deaths occurred. There were no significant differences in liver function (ALT, AST, and TP; P > 0.05) and kidney function (BUN, CRE, and UA; P > 0.05) in each group of mice. Compared to the control group, the model group of mice showed significantly decreased sucrose preference and significantly increased immobility time (P < 0.01 or P < 0.05). Compared with the model group, the mice in the PMC low, medium, and high dose groups showed a significant decrease in immobility time and a significant increase in sucrose preference. In the PMC-Compound-Target-Pathway-DD network, 54 active compounds, 83 common targets, and 13 major signaling pathways were identified for the treatment of DD. Molecular docking verified that the active compounds could effectively bind with the hub targets. PMC is a relatively safe antidepressant herbal medicine with its potential mechanism involving multiple compounds, targets, and pathways.

Efficacy of Biejiajian Pill on Intestinal Microbiota in Patients with Hepatitis B Cirrhosis/Liver Fibrosis: A Randomized Double-Blind Controlled Trial.

To analyze the efficacy of Biejiajian Pill (BJJP) on intestinal microbiota in patients with hepatitis B cirrhosis/liver fibrosis, and explore its relationship with liver fibrosis. This was a prospective, randomized double-blind controlled trial. Using the stratified block randomization method, 35 patients with hepatitis B liver cirrhosis/liver fibrosis were randomly assigned (1:1) to receive entecavir (0.5 mg/d) combined with BJJP (3 g/time, 3 times a day) or placebo (simulator as control, SC group, simulator 3 g/time, 3 times a day) for 48 weeks. Blood and stool samples were collected from patients at baseline and week 48 of treatment, respectively. Liver and renal functions as well as hematological indices were detected. Fecal samples were analyzed by 16S rDNA V3-V4 high-throughput sequencing, and intestinal microbiota changes in both groups before and after treatment were compared, and their correlations with liver fibrosis were analyzed. Compared with the SC group, there was no significant difference in liver function, renal function and hematology indices in the BJJP group, however, the improvement rate of liver fibrosis was higher in the BJJP group (94.4% vs. 64.7%, P=0.041). Principal coordinate analysis (PCoA) based on weighted Unifrac distance showed significant differences in intestinal microbiota community diversity before and after BJJP treatment (P<0.01 and P=0.003), respectively. After 48 weeks' treatment, the abundance levels of beneficial bacteria (Bifidobacteria, Lactobacillus, Faecalibacterium and Blautia) increased, whereas the abundance levels of potential pathogenic bacteria, including Escherichia coli, Bacteroides, Ruminococcus, Parabacteroides and Prevotella decreased, among which Ruminococcus and Parabacteroides were significantly positively correlated with degree of liver fibrosis (r=0.34, P=0.04; r=0.38, P=0.02), respectively. The microbiota in the SC group did not change significantly throughout the whole process of treatment. BJJP had a certain regulatory effect on intestinal microbiota of patients with hepatitis B cirrhosis/liver fibrosis (ChiCTR1800016801).

Simultaneous CSM-TACE with CalliSpheres® and partial splenic embolization using 8spheres® for hepatocellular carcinoma with hypersplenism: Early prospective multicenter clinical outcome.

Primary hepatocellular carcinoma is often complicated with hepatitis and liver cirrhosis. Some patients develop different degrees of splenomegaly, hypersplenism and hypohepatia due to the aggravation of liver cirrhosis, which to some extent interfere with the treatment of tumors and even affect the prognosis of patients. In this study, we prospectively evaluate the efficacy and safety of simultaneous CalliSpheres® microspheres transcatheter arterial chemoembolization (CSM-TACE) and partial splenic embolization (PSE) using 8spheres® for hepatocellular carcinoma (HCC) with hypersplenism. Ninety consecutive HCC patients with hypersplenism who underwent CSM-TACE were selected: 32 patients in CSM-TACE+PSE group, and 58 patients in CSM-TACE group. The peripheral blood cell counts (leukocyte, platelet (PLT), liver function and red blood cell (RBC)), CSM-TACE and/or PSE related complications, and the tumor control rate at 1 month after CSM-TACE were compared. The survival time and prognostic factors were also observed. Before CSM-TACE, there were no significant differences in sex, age, Child-Pugh grade, tumor size, and alpha-fetoprotein (AFP) between the two groups. After CSM-TACE, the PLT and white blood cell (WBC) counts in CSM-TACE+PSE group were significantly higher than those in the CSM-TACE group (P<0.05). There were no significant differences in RBC before and after treatment (P > 0.05). In the CSM-TACE group, there were no significant differences in WBC, PLT, and RBC before and after treatment (P > 0.05). There was no significant difference in liver function at 1 month after treatment between the two groups. The cholinesterase (CHE) level in the CSM-TACE+PSE group after CSM-TACE+PSE was obviously higher than that before CSM-TACE+PSE and higher than that in the CSM-TACE group (P<0.05). However, the level of CHE returned to the preoperative level 1 month after CSM-TACE in the CSM-TACE group. The objective response rate (ORR) and median overall survival (OS) in the CSM-TACE+PSE group were higher than those in the CSM-TACE group (P<0.05). The adverse reactions of the two groups were fever, abdominal pain, stomach discomfort, nausea, and vomiting, and no serious complications occurred. The degree of abdominal pain and fever in the experimental group was lower than that in the control group (P > 0.05). Simultaneous CSM-TACE and PSE using domestic embolization particles for HCC with hypersplenism have good safety and efficacy and has a low incidence of PSE-related adverse events, it is conducive to improving liver function reserve, and can further improve the median OS.

Liver Enzymes in a Cohort of Community-Dwelling Older Persons: Focus on Sex Contribution

Dysfunctions in liver metabolic activities may increase the risk of cognitive impairment and dementia. In a cohort of community-dwelling older persons investigated for a suspected cognitive decline, we studied the association between liver status and dementia, considering sex and frailty contribution. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations, and the AST/ALT ratio were used to assess liver function in 419 older adults (248 persons with dementia and 171 age- and sex-matched subjects without cognitive decline). Although the serum concentrations of the liver enzymes were in the physiologic range, patients with dementia showed lower ALT concentrations (p = 0.005) and higher AST/ALT ratios (p = 0.003) compared to controls. The same differences were found when comparing men with and without dementia (ALT, p = 0.009; AST/ALT ratio, p = 0.003) but disappeared in women. Curiously, comparing women and men with the same diagnosis, the ALT concentrations were lower (p = 0.008), and the AST/ALT ratio was higher (p = 0.001) in control women than men, whereas no significant difference was found between persons with dementia. In conclusion, in our cohort of older people living in the community, the association between serum aminotransferases and dementia was remarked. Moreover, our results support attention to sex difference in liver function, suggesting a role in the pathogenesis of dementia.

The Immunological Effect of Oxygen Carriers on Normothermic Ex Vivo Liver Perfusion.

IntroductionNormothermic ex vivo liver perfusion (NEVLP) is an organ preservation method that allows liver graft functional assessment prior to transplantation. One key component of normothermic perfusion solution is an oxygen carrier to provide oxygen to the liver to sustain metabolic activities. Oxygen carriers such as red blood cells (RBCs) or hemoglobin-based oxygen carriers have an unknown effect on the liver-resident immune cells during NEVLP. In this study, we assessed the effects of different oxygen carriers on the phenotype and function of liver-resident immune cells.MethodsAdult Lewis rat livers underwent NEVLP using three different oxygen carriers: human packed RBCs (pRBCs), rat pRBCs, or Oxyglobin (a synthetic hemoglobin-based oxygen carrier). Hourly perfusate samples were collected for downstream analysis, and livers were digested to isolate immune cells. The concentration of common cytokines was measured in the perfusate, and the immune cells underwent phenotypic characterization with flow cytometry and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The stimulatory function of the liver-resident immune cells was assessed using mixed lymphocyte reactions.ResultsThere were no differences in liver function, liver damage, or histology between the three oxygen carriers. qRT-PCR revealed that the gene expression of nuclear factor κ light chain enhancer of activated B cells (NF-kB), Interleukin (IL-1β), C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 7 (CCL7), and CD14 was significantly upregulated in the human pRBC group compared with that in the naive, whereas the rat pRBC and Oxyglobin groups were not different from that of naive. Flow cytometry demonstrated that the cell surface expression of the immune co-stimulatory protein, CD86, was significantly higher on liver-resident macrophages and plasmacytoid dendritic cells perfused with human pRBC compared to Oxyglobin. Mixed lymphocyte reactions revealed increased allogeneic T-cell proliferation in the human and rat pRBC groups compared to that in the Oxyglobin group.ConclusionsLiver-resident immune cells are important mediators of rejection after transplantation. In this study, we show that the oxygen carrier used in NEVLP solutions can affect the phenotype of these liver-resident immune cells. The synthetic hemoglobin-based oxygen carrier, Oxyglobin, showed the least amount of liver-resident immune cell activation and the least amount of allogeneic proliferation when compared to human or rat pRBCs. To mitigate liver-resident immune cell activation during NEVLP (and subsequent transplantation), Oxyglobin may be an optimal oxygen carrier.

A comparative study of efficacy and safety of transarterial chemoembolization with CalliSpheres and conventional transarterial chemoembolization in treating unresectable intrahepatic cholangiocarcinoma patients.

Objective: Previous studies reported that drug-eluting beads transarterial chemoembolization (DEB-TACE) with CalliSpheres is effective and safe to treat hepatocellular carcinoma patients and metastatic liver cancer patients, however few studies reported its clinical application in intrahepatic cholangiocarcinoma (ICC) patients. Therefore, this study aimed to compare the efficacy between DEB-TACE versus conventional transarterial chemoembolization (cTACE) in unresectable ICC patients.Methods: Between January 2016 and June 2020, 89 patients with unresectable ICC were retrospectively analyzed, and enrolled into DEB-TACE group (N=40) and cTACE group (N=49) based on the transarterial treatment. Treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Time to progression (TTP) and overall survival (OS) were analyzed by using the Kaplan-Meier curve. Factors affecting OS and TTP were determined by Cox's proportional hazards regression model.Results: DEB-TACE group showed higher DCR (87.5% vs. 65.3%, P=0.011), while similar ORR (67.5% vs. 57.1%, P=0.317) compared to cTACE group. Furthermore, DEB-TACE group had longer OS (median 10 months vs 6 months, P=0.006), while similar TTP compared to cTACE group (median 4 months vs 2 months, P=0.098). After adjustment by multivariant Cox's regression, DEB-TACE (versus cTACE) independently correlated with longer OS (P=0.031). Further subgroup analyses displayed that OS was prolonged in DEB-TACE group compared to cTACE group in patients with multiple tumors (P=0.032) and patients with no lymph node metastasis (P=0.023). Apart from abdominal pain, no difference of adverse events between the two groups was observed. There was no difference in liver function (Bilirubin, Albumin, Prothrombin time) before and after treatment (4 weeks) in both groups.Conclusion: In patients with unresectable ICC, DEB-TACE significantly improved the OS when compared with cTACE and was well tolerated.

The transcatheter arterial chemoembolization combined with targeted nanoparticle delivering sorafenib system for the treatment of microvascular invasion of hepatocellular carcinoma

ABSTRACT to explore the value of transcatheter arterial chemoembolization (TACE) combined with targeted nanoparticle delivery system for sorafenib (SFB) to treat hepatocellular carcinoma (HCC) with microvascular invasion. 42 HCC patients with microvascular invasion after liver cancer surgery were selected from our hospital from December 2020 and February 2021. Patients were divided into experimental group and control group based on their willingness. Patients in experimental group (18 cases) were treated with combination therapy of TACE and Ab-SFB-NP system; while patients in control group (24 cases) took TACE and non-nano drug delivery system. There was no obvious difference in liver function and blood test results between two groups of patients before treatment and one month after treatment (P > 0.05). Three months after treatment, differences of alanine aminotransferase (ALT) were statistically significant (P < 0.05); while differences of other test results were not (P > 0.05). The disease control rate (DCR) of patients in experimental group was higher slightly (P > 0.05). The incidence of adverse reactions of patients in experimental group was lower than the control group and the differences were statistically significant (P < 0.05). After three months of TACE, the DCR in the experimental group was significantly higher compared to control group. The toxic reactions of taking SFB with Ab-SFB-NP nano-drug delivery system mainly included hand-foot syndrome, diarrhea, and bleeding, the toxic reactions were mainly at level 1 ~ 2. After symptomatic treatment, the toxicity was effectively controlled, so the security was high.

Survival and outcomes for co-infection of chronic hepatitis C with and without cirrhosis and COVID-19: A multicenter retrospective study.

BACKGROUNDChronic liver disease, particularly cirrhosis, is associated with worse outcomes in patients infected with coronavirus disease 2019 (COVID-19).AIMTo assess outcomes of COVID-19 infection among patients with pre-existing hepatitis C with or without liver cirrhosis.METHODSThis multicenter, retrospective cohort study included all cases of confirmed co-infection of severe acute respiratory syndrome coronavirus 2 and chronic hepatitis C with or without liver cirrhosis who were admitted to six hospitals (Al-Sahel Hospital, Al-Matareya Hospital, Al-Ahrar Hospital, Ahmed Maher Teaching Hospital, Al-Gomhoreya Hospital, and the National Hepatology and Tropical Medicine Research Institute) affiliated with the General Organization for Teaching Hospitals and Institutes in Egypt. Patients were recruited from May 1, 2020, to July 31, 2020. Demographic, laboratory, imaging features, and outcomes were collected. Multivariate regression analysis was performed to detect factors affecting mortality.RESULTSThis retrospective cohort study included 125 patients with chronic hepatitis C and COVID-19 co-infection, of which 64 (51.20%) had liver cirrhosis and 40 (32.00%) died. Fever, cough, dyspnea, and fatigue were the most frequent symptoms in patients with liver cirrhosis. Cough, sore throat, fatigue, myalgia, and diarrhea were significantly more common in patients with liver cirrhosis than in non-cirrhotic patients. There was no difference between patients with and without cirrhosis regarding comorbidities. Fifteen patients (23.40%) with liver cirrhosis presented with hepatic encephalopathy. Patients with liver cirrhosis were more likely than non-cirrhotic patients to have combined ground-glass opacities and consolidations in CT chest scans: 28 (43.75%) vs 4 (6.55%), respectively (P value < 0.001). These patients also were more likely to have severe COVID-19 infection, compared to patients without liver cirrhosis: 29 (45.31%) vs 11 (18.04%), respectively (P value < 0.003). Mortality was higher in patients with liver cirrhosis, compared to those with no cirrhosis: 33 (51.56%) vs 9 (14.75%), respectively (P value < 0.001). All patients in Child-Pugh class A recovered and were discharged. Cirrhotic mortality occurred among decompensated patients only. A multivariate regression analysis revealed the following independent factors affecting mortality: Male gender (OR 7.17, 95%CI: 2.19–23.51; P value = 0.001), diabetes mellitus (OR 4.03, 95%CI: 1.49–10.91; P value = 0.006), and liver cirrhosis (OR 1.103, 95%CI: 1.037–1.282; P value < 0.0001). We found no differences in liver function, COVID-19 disease severity, or outcomes between patients who previously received direct-acting antiviral therapy (and achieved sustained virological response) and patients who did not receive this therapy.CONCLUSIONPatients with liver cirrhosis are susceptible to higher severity and mortality if infected with COVID-19. Male gender, diabetes mellitus, and liver cirrhosis are independent factors associated with increased mortality risk.

Pretreatment Neutrophil-to-Lymphocyte Ratio as a Predictive Marker of Response to Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma.

Background: Combination therapy with anti-programmed death-ligand 1 monoclonal antibody atezolizumab plus anti-vascular endothelial growth factor agent bevacizumab (Atezo/Bev) was approved in 2020 as a first-line treatment for unresectable hepatocellular carcinoma (HCC). Atezo/Bev therapy is relatively well tolerated; however, factors that can predict its response have not yet been reported. Thus, we aimed to investigate whether the pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict the therapeutic response in patients with HCC treated with Atezo/Bev therapy. Methods: We analyzed the course of 40 patients with HCC who received Atezo/Bev therapy at our hospital and attempted to identify pretreatment factors that could predict response by comparing those who achieved disease control with those who did not. Results: The pretreatment NLR value in patients who achieved disease control was significantly lower than that in patients with disease progression (2.47 vs. 4.48, p = 0.013). Using the optimal NLR cut-off value for predicting response (3.21) determined by receiver operating characteristic curve analysis, patients with NLR ≤ 3.21 had significantly better progression-free survival than those with NLR > 3.21 (p < 0.0001), although there were no significant differences in liver function or tumor-related background factors between the two groups. Conclusions: The pretreatment NLR value may be a useful predictor of response to Atezo/Bev therapy for HCC.

Exposure-time-dependent subcellular staging of gold nanoparticles deposition and vesicle destruction in mice livers

Several advances in nanomedicine have been accompanied by rising concerns about the bioaccumulation and toxicity of gold nanoparticles (AuNPs). Here, we assessed the in vivo fate of diversely sized AuNPs that were injected into mice as a computed tomography contrast agent and examined with multi-scale analyses across the organ, tissue, cell, and subcellular levels. After focusing on the strong detected accumulation in livers, our data revealed a set of three clear, exposure-time-dependent patterns based on i) AuNPs deposit morphology and ii) readily identifiable phenotypes for AuNP-impacted subcellular vesicles. Importantly, we detected no obvious differences in liver function, liver cell apoptosis, or autophagy upon exposure to AuNPs. Thus, our study illustrates an accessible experimental and high-resolution data interpretation framework for quickly obtaining and contextualizing informative trends about any AuNP-triggered patterns of subcellular damage in nanomedicine studies; these can help guide cytotoxity and safety testing of diagnostic nanomedical technologies.

A human liver chimeric mouse model for non-alcoholic fatty liver disease

Background & AimsThe accumulation of neutral lipids within hepatocytes underlies non-alcoholic fatty liver disease (NAFLD), which affects a quarter of the world’s population and is associated with hepatitis, cirrhosis, and hepatocellular carcinoma. Despite insights gained from both human and animal studies, our understanding of NAFLD pathogenesis remains limited. To better study the molecular changes driving the condition we aimed to generate a humanised NAFLD mouse model.MethodsWe generated TIRF (transgene-free Il2rg-/-/Rag2-/-/Fah-/-) mice, populated their livers with human hepatocytes, and fed them a Western-type diet for 12 weeks.ResultsWithin the same chimeric liver, human hepatocytes developed pronounced steatosis whereas murine hepatocytes remained normal. Unbiased metabolomics and lipidomics revealed signatures of clinical NAFLD. Transcriptomic analyses showed that molecular responses diverged sharply between murine and human hepatocytes, demonstrating stark species differences in liver function. Regulatory network analysis indicated close agreement between our model and clinical NAFLD with respect to transcriptional control of cholesterol biosynthesis.ConclusionsThese NAFLD xenograft mice reveal an unexpected degree of evolutionary divergence in food metabolism and offer a physiologically relevant, experimentally tractable model for studying the pathogenic changes invoked by steatosis.Lay summaryFatty liver disease is an emerging health problem, and as there are no good experimental animal models, our understanding of the condition is poor. We here describe a novel humanised mouse system and compare it with clinical data. The results reveal that the human cells in the mouse liver develop fatty liver disease upon a Western-style fatty diet, whereas the mouse cells appear normal. The molecular signature (expression profiles) of the human cells are distinct from the mouse cells and metabolic analysis of the humanised livers mimic the ones observed in humans with fatty liver. This novel humanised mouse system can be used to study human fatty liver disease.

Effects of vasoactive drugs on hepatic and intestinal circulation and intestinal barrier in patients with septic shock

In this study, 60 patients with septic shock were selected over the course of 1 year, and the effects of dopamine and norepinephrine combined with dobutamine on hepatic and intestinal...

Physiologically inspired culture medium prolongs the lifetime and insulin sensitivity of human hepatocytes in micropatterned co-cultures

Given significant species-specific differences in liver functions, cultures of primary human hepatocytes (PHHs) are useful for assessing drug metabolism and to mitigate the risk of drug-induced hepatotoxicity in humans. While significant advances have been made to keep PHHs highly functional for 2–4 weeks in vitro, especially upon co-culture with both liver- and non-liver-derived non-parenchymal cells (NPCs), the functional lifespan of PHHs is 200–400 days in vivo. Therefore, it is desirable to determine culture conditions that can further prolong PHHs functions in vitro for modeling chronic drug exposure, disease pathogenesis, and to provide flexibility to the end-user for staggering drug incubations across multiple culture batches. Most PHH culture platforms utilize supraphysiologic levels of glucose and insulin and bovine-derived serum when including NPCs, which can alter PHH functions. Therefore, here we developed a culture medium containing physiologic levels of glucose (5 mM), insulin (500 pM), and human serum (10 % v/v) and tested its effects on micropatterned co-cultures (MPCCs) in which PHHs are organized onto collagen domains of empirically optimized dimensions and surrounded by 3T3-J2 murine fibroblasts that express liver-like molecules and induce higher PHH functions than liver-derived NPCs. Our physiologically-inspired culture medium allowed better retention of PHH morphology, polarity, and functions (albumin and urea, cytochrome-P450 activities, and sensitivity to insulin-mediated inhibition of gluconeogenesis) for up to 10 weeks relative to the traditional medium. Finally, PHHs in the physiologic medium displayed clinically-relevant responses to prototypical drugs for hepatoxicity and cytochrome-P450 induction. Ultimately, our physiologic culture medium could find broader utility for the continued development of PHH-NPC co-cultures for drug development, investigating the effects of patient-derived sera on PHH functions and disease phenotypes, and for use in cell-based therapies.

Metabolic alterations in dairy cows with subclinical ketosis after treatment with carboxymethyl chitosan-loaded, reduced glutathione nanoparticles.

BackgroundSubclinical ketosis (SCK) causes economic losses in the dairy industry because it reduces the milk production and reproductive performance of cows.Hypothesis/ObjectivesTo evaluate whether carboxymethyl chitosan‐loaded reduced glutathione (CMC‐rGSH) nanoparticles can alleviate the incidence or degree of SCK in a herd.AnimalsHolstein dairy cows 21 days postpartum (n = 15).MethodsThe trial uses a prospective study. Five cows with serum β‐hydroxybutyric acid (BHBA) ≥1.20 mmol/L and aspartate aminotransferase (AST) <100 IU/L were assigned to group T1, 5 cows with BHBA ≥1.20 mmol/L and AST >100 IU/L to group T2, and 5 cows with BHBA <1.00 mmol/L and AST <100 IU/L to group C. Carboxymethyl chitosan‐loaded reduced glutathione (0.012 mg/kg body weight per cow) was administered to cows in T1 and T2 once daily via jugular vein for 6 days after diagnosis. Serum from all groups were collected 1 day before administration, then on days 1, 3, 5, 7, 10, and 15 after administration to determine the changes in biochemical index and 1H‐NMR.ResultsThe difference in liver function or energy metabolism indices in T1, T2, and C disappeared at day 7 and day 10 after the administration (P > .05). Valine, lactate, alanine, lysine, creatinine, glucose, tyrosine, phenylalanine, formate, and oxalacetic acid levels, and decrease in isoleucine, leucine, proline, acetate, trimethylamine N‐oxide, glycine, and BHBA levels were greater (P < .05) at day 7 than day 0 for cows in T2.Conclusions and Clinical ImportanceCarboxymethyl chitosan‐loaded reduced glutathione treatment might alleviate SCK by enhancing gluconeogenesis and reducing ketogenesis in amino acids.

Assessing Non-Invasive Liver Function in Patients with Intestinal Failure Receiving Total Parenteral Nutrition-Results from the Prospective PNLiver Trial.

Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can progress undetected by standard laboratory tests to intestinal failure associated liver disease (IFALD). The aim of this longitudinal study is to evaluate the ability of non-invasive liver function tests to assess liver function following the initiation of PN. Twenty adult patients with IF were prospectively included at PN initiation and received scheduled follow-up assessments after 6, 12, and 24 months between 2014 and 2019. Each visit included liver assessment (LiMAx [Liver Maximum Capacity] test, ICG [indocyanine green] test, FibroScan), laboratory tests (standard laboratory test, NAFLD [non-alcoholic fatty liver disease] score, FIB–4 [fibrosis-4] score), nutritional status (bioelectrical impedance analysis, indirect calorimetry), and quality of life assessment. The patients were categorized post-hoc based on their continuous need for PN into a reduced parenteral nutrition (RPN) group and a stable parenteral nutrition (SPN) group. While the SPN group (n = 9) had significantly shorter small bowel length and poorer nutritional status at baseline compared to the RPN group (n = 11), no difference in liver function was observed between the distinct groups. Over time, liver function determined by LiMAx did continuously decrease from baseline to 24 months in the SPN group but remained stable in the RPN group. This decrease in liver function assessed with LiMAx in the SPN group preceded deterioration of all other investigated liver function tests during the study period. Our results suggest that the liver function over time is primarily determined by the degree of intestinal failure. Furthermore, the LiMAx test appeared more sensitive in detecting early changes in liver function in comparison to other liver function tests.

Ramucirumab for patients with intermediate-stage hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): Pooled results from two phase III studies (REACH and REACH-2).

549 Background: Intermediate-stage HCC, as defined as Barcelona Clinic Liver Cancer (BCLC) Stage B, is a heterogeneous disease in terms of liver function and tumor load. REACH (NCT01140347) and REACH-2 (NCT02435433) investigated ramucirumab (RAM) in patients (pts) with HCC after prior sorafenib (SOR), with REACH-2 enrolling only pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: All pts had HCC (BCLC stage C or B disease refractory/not amenable to locoregional therapy), Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or Placebo (P) Q2W. A pooled meta-analysis of independent pt data (stratified by study) from REACH-2 and REACH (AFP ≥400 mg/mL) was performed. Prognosis of BCLC staging in overall survival (OS) was evaluated by multivariate Cox PH model (adjusted for baseline AFP and treatment (trt) arm); Trt effects in BCLC stage B and C by Cox PH model; median OS/PFS were estimated by Kaplan-Meier method. Objective response rate (ORR) per RECIST v1.1, disease control rate (DCR), and adverse events (AEs) were also reported by BCLC. Liver function was assessed at baseline and prior to each trt with the Albumin-Bilirubin (ALBI) linear predictor. Results: Baseline characteristics were generally balanced between trt arms in each BCLC stage. BCLC staging trended as an independent prognosis factor for OS [B v C; HR = 0.756 (0.546, 1.046)]. A consistent trt benefit for RAM v P was observed across staging (Table). Grade ≥3 AEs were consistent with observations from both individual studies; hypertension was the most frequent grade ≥3 AE. No difference in liver function, as measured by ALBI, was observed between trt arms in either BCLC stage. Conclusions: Acknowledging limitations of sample size, RAM provided a survival benefit irrespective of BCLC stage. RAM was well tolerated and did not alter liver function compared to P. Clinical trial information: NCT01140347, NCT02435433. [Table: see text]