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The risk factors for drug-induced liver injury (DILI) involve host factors (including general non-genetic factors and idiosyncratic genetic and immune factors), drug-related factors, and environmental factors. The pathogenesis of DILI can be classified as intrinsic (or direct) hepatotoxicity, idiosyncratic hepatotoxicity, and indirect hepatotoxicity, as well as tumorigenicity and carcinogenicity of some drugs to the liver. The pathogenesis of different types of hepatotoxicity not only has significant differences, but also has internal correlation at multiple links. The three-step model centered on mitochondrial permeability transition (MPT) and a two-stage model with liver cell regeneration and liver tissue repair capacity as the determinants of different outcomes display the mechanism progress of DILI from different perspectives. Clarification of the complex pathogenesis of DILI needs long-term collection of clinical cases and systematic studies, which is of great significance for the scientific prevention, diagnosis, and treatment of DILI.
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BACKGROUND: Liver fibrosis has higher morbidity and mortality. Activation and proliferation of hepatic stellate cells is a key link in the progression of liver fibrosis. At present, there are still no effective anti-fibrosis agents targeting single links or targets.OBJECTIVE: To analyze the effect of human adipose stem cells derived exosomes on rats with liver fibrosis induced by carbon tetrachloride. METHODS: Human adipose stem cells were obtained from healthy people by enzyme dissolution method. After in vitro culture, human adipose stem cells derived exosomes were obtained by multiple ultrafiltration. Different concentrations of exosomes were used to treat the hepatic stellate cells activated by transforming growth factor β1. The human adipose stem cells activated by transforming growth factor β1 were treated with different concentrations of exosomes. The expression of α-smooth actin in the cells was detected by quantitative PCR, and the growth and apoptosis of activated hepatic stellate cells were detected by CCK-8 and flow cytometry respectively. Rat models of liver fibrosis were established by intraperitoneal injection of carbon tetrachloride and treated by tail vein injection of exosomes. Rat liver function, serum levels of type III procollagen and type IV collagen, and Ishak score were determined. Semi-quantitative analysis of liver fibrosis was performed. The expression levels of tissue inhibitor of matrix metalloproteinase-1, matrix metalloproteinase 9 and α-smooth actin in liver tissue were measured by immunofluorescence method. The study protocol was approved by the Animal Ethics Committee and Medical Ethics Committee, Tongji University, China in January, 2017. RESULTS AND CONCLUSION: Human adipose stem cells derived exosomes inhibited the proliferation of activated hepatic stellate cells. The possible mechanism is to inhibit the proliferation of activated macrophages, reduce the production of collagen fibers, α-smooth actin actin, and tissue inhibitor of matrix metalloproteinase-1, and to increase the expression of matrix metalloproteinase 9. These findings suggest that exosomes can be used to treat carbon tetrachloride induced liver fibrosis.
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Objective@#To probe into the mechanism and interventional effects of silybin-phospholipid complex on amiodarone-induced steatosis in mice.@*Methods@#Eight-week-old male C57BL/6 mice were divided into three groups (5 mice in each group): a control group (WT) with normal diet, a model group with amiodarone 150mg/kg/d by oral gavage (AM), and an intervention group on amiodarone 150mg/kg/d combined with silybin-phospholipid complex(AM+SILIPHOS. All mice were fed their assigned diet for one week. Then, one week later, serum alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol and high-density lipoprotein were detected of each group. A liver pathological change was observed by oil red O and H&E staining. Ultrastructural pathological changes of hepatocytes were observed to evaluate the intervention effect by transmission electron microscopy. RT-q PCR was used to detect the expression of peroxisome proliferator-activated receptor alpha and its regulated lipid metabolism genes CPTI, CPTII, Acot1, Acot2, ACOX, Cyp4a10 and Cyp4a14 in liver tissues. Intra-group comparison was done by paired t-test. One-way ANOVA was used for comparison between groups and semi-quantitative data were tested using Mann-Whitney U test.@*Results@#Oil Red O and H&E staining results of liver tissue in the intervention group showed that intrahepatic steatosis was significantly reduced when compared to model group. Transmission electron microscopy showed that the model group had pyknotic nuclei, mitochondrial swelling, structural damage, and lysosomal degradation whereas the intervention group had hepatic nucleus without pyknosis, reduced mitochondrial swelling and slight structural damage than that of model group. RT-q PCR results showed that the expression of peroxisome proliferator-activated receptor alpha, CPTI, CPTII, Acot1, Acot2, ACOX, Cyp4a10 and Cyp4a14 were increased in the model group but the expression of CPTI, Cyp4a14, Acot1 and peroxisome proliferator-activated receptor alpha were decreased in the intervention group (P < 0.05).@*Conclusion@#Silybin-phospholipid complex can alleviate amiodarone-induced steatosis, and its mechanism may play a role in protecting mitochondrial function and regulating fatty acid metabolism. Thus, silybin-phospholipid complex has potential intervention effect on amiodarone-induced fatty liver.
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The 2019 European Association for the Study of the Liver (EASL) Clinical Practice Guidelines (hereinafter referred to as the EASL Guidelines) extracted the required evidence from detailed research materials, and rigorously graded and condensed the varying strengths of evidence into 32 recommendations and 14 statements (recommendations and reminders) for drug-induced Liver Injury (DILI). This guideline has important reference values for helping clinicians to further improve their understanding of DILI and the level of clinical diagnosis, treatment and prevention; however, there are still several issues worthy of further discussion.
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Cholestatic liver disease (CSLD) is a group of liver diseases which can cause cholestasis and has a complex etiology. Its pathogenesis remains unclear, and there are still no effective treatment measures. In the recent decade, new achievements have been made on various aspects of CSLD, which provides more help to accurate diagnosis and treatment and reflects many pending issues which need further research. This article introduces the research advances and problems in CSLD from the following six aspects: the “ascending” pathophysiology of CSLD, mechanisms of cholestasis-induced liver fibrosis and related management measures, association of enterohepatic circulation and intestinal microbiota with CSLD, pathogenesis and diagnosis/treatment of drug-induced cholestasis, pathogenesis and management of liver failure-associated cholestasis, and research advances in treatment targets and drug research and development for CSLD.
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Due to a lack of specific biomarkers, the diagnosis of drug -induced liver injury (DILI) mainly depends on the method of exclusion.The Roussel Uclaf Causality Assessment Method (RUCAM) scale is the most widely used causality assessment scale and is relatively objective, but it is still waiting for further improvement.Another method is global introspection or expert opinion , which is relatively subjective,and the simplified global introspection method is commonly used in clinical practice .The Structured Expert Opinion Procedure (SEOP) created by the US DILI network (DILIN) is very complicated and time -consuming and thus cannot be used in clinical practice .The drug rechallenge test (DRT) with a positive result is considered the gold standard for the diagnosis of DILI , but DILI cannot be excluded based on the negative result of DRT.The value of lymphocyte transformation test (LTT), modified LTT, monocyte -derived hepatocyte -like cell lactate -dehydrogenase release test, and various predictive models for drug hepatotoxicity in the diagnosis of DILI awaits further assessment .The differential diagnosis of autoimmune -mediated DILI and traditional autoimmune liver diseases usually depends on liver biopsy , the type and titer of autoantibody, and response to glucocorticoids.Reasonable timing of drug withdrawal and application of anti -inflammatory liver -protecting drugs may help most DILI patients recover .Generally, the prophylactic use of anti -inflammatory liver -protecting drugs is not recommended, except in special situations.In -depth studies are needed for the precise diagnosis and prevention /treatment of DILI.
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At present, Drug -induced liver injury(DILI) has become the most common cause of acute liver injury in clinical practice .This article elaborates on the pathogenesis of DILI , new biomarkers, liver tolerance to drug toxicity, adaptability and susceptibility, and testing threshold of alanine aminotransferase .Meanwhile, we should understand the development history of diagnostic scale , develop unified standards and understanding, and attach importance to DILI induced by medicinal herbs and dietary supplements , and in -depth studies on the pathogenesis of DILI should be performed to prevent or reduce DILI .There are several problems in DILI studies in China and obvious gaps between China and foreign countries, with a lack of basic research and blanks in clinical aspects .Therefore, we must strive to keep up with international research so that drugs can better serve the human .
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Objective@#To investigate the clinical effect and safety of long-acting pegylated interferon-α-2b (Peg-IFN-α-2b) (Y shape, 40 kD) injection (180 μg/week) in the treatment of HBeAg-positive chronic hepatitis B (CHB) patients, with standard-dose Peg-IFN-α-2a as positive control.@*Methods@#This study was a multicenter, randomized, open-label, and positive-controlled phase III clinical trial. Eligible HBeAg-positive CHB patients were screened out and randomized to Peg-IFN-α-2b (Y shape, 40 kD) trial group and Peg-IFN-α-2a control group at a ratio of 2:1. The course of treatment was 48 weeks and the patients were followed up for 24 weeks after drug withdrawal. Plasma samples were collected at screening, baseline, and 12, 24, 36, 48, 60, and 72 weeks for centralized detection. COBAS® Ampliprep/COBAS® TaqMan® HBV Test was used to measure HBV DNA level by quantitative real-time PCR. Electrochemiluminescence immunoassay with Elecsys kit was used to measure HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe). Adverse events were recorded in detail. The primary outcome measure was HBeAg seroconversion rate after the 24-week follow-up, and non-inferiority was also tested. The difference in HBeAg seroconversion rate after treatment between the trial group and the control group and two-sided confidence interval (CI) were calculated, and non-inferiority was demonstrated if the lower limit of 95% CI was > -10%. The t-test, chi-square test, or rank sum test was used according to the types and features of data.@*Results@#A total of 855 HBeAg-positive CHB patients were enrolled and 820 of them received treatment (538 in the trial group and 282 in the control group). The data of the full analysis set showed that HBeAg seroconversion rate at week 72 was 27.32% in the trial group and 22.70% in the control group with a rate difference of 4.63% (95% CI -1.54% to 10.80%, P = 0.1493). The data of the per-protocol set showed that HBeAg seroconversion rate at week 72 was 30.75% in the trial group and 27.14% in the control group with a rate difference of 3.61% (95% CI -3.87% to 11.09%, P = 0.3436). 95% CI met the non-inferiority criteria, and the trial group was non-inferior to the control group. The two groups had similar incidence rates of adverse events, serious adverse events, and common adverse events.@*Conclusion@#In Peg-IFN-α regimen for HBeAg-positive CHB patients, the new drug Peg-IFN-α-2b (Y shape, 40 kD) has comparable effect and safety to the control drug Peg-IFN-α-2a.
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Objective@#To investigate the efficacy and safety of the new investigational drug pegylated interferon α-2b (Peg-IFN-α-2b) (Y shape, 40 kD) injection (180 µg/week) combined with ribavirin in the treatment of patients with genotype 1/6 chronic hepatitis C (CHC), with standard-dose Peg-IFN-α-2a combined with ribavirin as a positive control.@*Methods@#A multicenter, randomized, open-label, and positive-controlled phase III clinical trial was performed. Eligible patients with genotype 1/6 CHC were screened out and randomly divided into Peg-IFN-α-2b(Y shape, 40kD) group and Peg-IFN-α-2a group at a ratio of 2:1. The patients in both groups were given oral ribavirin for 48 weeks in addition and then followed up for 24 weeks after drug withdrawal. Abbott Real Time HCV Genotype II was used to determine HCV genotype, and Cobas TaqMan quantitative real-time PCR was used to measure HCV RNA level at 0, 4, 12, 24, 48, and 72 weeks. Adverse events were recorded in detail. The primary efficacy endpoint was sustained virological response (SVR), and a non-inferiority test was also performed.@*Results@#A total of 561 patients with genotype 1/6 CHC were enrolled, among whom 529 received treatment; 90.9% of these patients had genotype 1 CHC. The data of the full analysis set showed that SVR rate was 69.80% (95% CI 65.00%-74.60%) in the trial group and 74.16% (95% CI 67.73%-80.59%) in the control group (P = 0.297 0). The data of the per protocol set (PPS) showed that SVR rate was 80.63% (95% CI 76.04%-85.23%) in the trial group and 81.33% (95% CI 75.10%-87.57%) in the control group (P = 0.849 8), and the 95% CI of rate difference conformed to the non-inferiority standard. The analysis of the PPS population showed that of all subjects, 47.9% achieved rapid virologic response, with a positive predictive value of 93.8%. The incidence rate of adverse events was 96.30% in the trial group and 94.94% in the control group, and the incidence rate of serious adverse events was 5.13% in the trail group and 5.06% in the control group.@*Conclusion@#In the regimen of Peg-IFN-α combined with ribavirin for the treatment of genotype 1/6 CHC, the new investigational drug Peg-IFN-α-2b(Y shape, 40 kD) has comparable clinical effect and safety to the control drug Peg-IFN-α-2a.
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BACKGROUND: It has been believed mesenchymal stem cells (MSCs) play a role in treatment through paracrine mechanism. Various side effects such as embolism, tumorigenesis and immunological reaction caused by direct injection of MSCs can be avoided by extracting MSC lysate. However, there is a larger difference in current collection methods and standards of MSC lysate. OBJECTIVE: To compare repeated freeze-thaw and ultrasonication for the collection of lysate of MSCs. METHODS: Adipose-derived mesenchymal stem cells (ADMSCs) were isolated from the abdominal subcutaneous fat of healthy individuals, and purified with adherence screening method, followed by in vitro amplification using fetal bovine serum medium. The common surface makers of these cells were tested by flow cytometry (1×109, 2×109, 4×109/L). Repeated freeze-thaw and ultrasonication were employed for cell cytoclasis at three different densities respectively in saline and double distilled water, and a comprehensive comparison was performed on cytoclasis rate and the content of protein in cell lysate between the two methods. RESULTS AND CONCLUSION: (1) ADMSCs obtained from in vitro isolated human adipose tissue grew in a swirl or radial pattern with a homogenous size and neat arrangement. CD44, CD90, CD105 and other commonly used surface markers were highly expressed. (2) The study for optimization of lysate collection revealed that the higher cell density implicated a longer time for cell wall disruption and cytoclasis, as well as significantly increased cytoclasis rate. (3) BCA protein assay showed that the highest content of protein was obtained in saline solvent using ultrasonication method. Comprehensive analysis on the results leads to a conclusion that ultrasonication method with saline as the solvent is the optimized method for extraction of ADMSCs lysate, and the cell concentration of less than 4×109/L is recommended.
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<p><b>OBJECTIVE</b>To investigate the epidemiological status of cholestasis in first-hospitalized patients with chronic liver disease in Shanghai, and to provide a scientific basis for developing prevention and treatment measures.</p><p><b>METHODS</b>From April 2005 to September 2014, 5,146 first-hospitalized patients in Shanghai with a diagnosis of chronic liver disease were enrolled in this study. Clinical data of the 4,660 patients who fit the study criteria for participation were collected for retrospective analysis.Diagnosis of cholestasis was made according to serum alkaline phosphatase (ALP) levels higher than 1.5 times the upper limit normal (ULN) and gamma-glutamyltransferase (GGT) levels higher than 3 times the ULN. The incidence rate of cholestasis was assessed for relation to age, sex, etiology, and type of liver disease, and statistically compared to the general clinical data and specific biochemical indicators with potential sex-related differences. T-test and chi-square test were performed for the statistical analyses.</p><p><b>RESULTS</b>Of the 4,660 study participants, 10.26% had cholestasis; the prevalence of cholestasis increased with increasing age in male patients. The distribution of the cholestasis incidence according to the type of chronic liver disease was: 75.00%, primary sclerosing cholangitis; 42.86%, primary biliary cirrhosis; 35.97%, hepatic tumor; 30.77%, autoimmune hepatitis; 28.31%, drug-induced liver disease; 16.46%, alcoholic hepatitis; 13.98%, cryptogenic cirrhosis; 12.99%, schistosomal cirrhosis; 7.53%, alcoholic cirrhosis; 7.32%, mixed cirrhosis; 5.94%, viral liver cirrhosis; 2.70%, nonalcoholic fatty liver disease. There was no significant difference in the prevalence of cholestasis between the two sexes. In the patients with cholestasis, the levels of GGT and total bilirubin were significantly different between the two sexes.</p><p><b>CONCLUSION</b>The incidence rate of cholestasis in first-hospitalized patients with chronic liver disease was 10.26%, and the rate increased with increased age. Patients with primary sclerosing cholangitis or primary biliary cirrhosis had higher incidence rates of cholestasis. Incidence rates of cholestasis of the various chronic liver diseases were not related to sex.</p>
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Humans , Male , Bilirubin , China , Cholestasis , Chronic Disease , Incidence , Liver Diseases , Prevalence , Retrospective Studies , gamma-GlutamyltransferaseABSTRACT
Objective Estimating clinical effects of the Therapy of Potassium L-aspartate Injection on Hypokalemia.Methods These hypolalemia patients from the Renji hospital of Shanghai Jiaotong University and Other Two Hospitals,and from March 2007 to May 2008,which were caused from various kinds of reasons.The test group (42 patients) were intravenous dripped by using three rami potassium L-aspartate injection added in 5% Glucose (or saline) 750 mL,the control group (44 patients) were gived two rami chloratum Kalium injection added in 5% Glucose (or saline) 750 mL,the Kalium were 1.10 g/d in both groups,once per day,time of therapy was 7 day.Results The test and control groups effective power after therapy were 86.67% and 91.11%,respectively,there was no significant difference (P=0.3998).The Kalium dose of test group was advanced from (3.18?0.23) mmol/L before testing to (3.73?0.37) mmol/L after therapy,the elevated average was (0.61?0.46)mmol/L,and there was no significant difference (P=0.4722).The accumulation power of Kalium recovery were (51.11?7.45)%,(77.78?6.20)%,(86.67?5.07)%,at the second,the fored and the sevened day,respectively.There was no significant difference between the two groups (P=0.1430).Conclusion The clinical effect was correspond between three rami potassium L-aspartate injection added in 5% Glucose (or saline) 750 ml and the Isodose chloratum Kalium injection,by once per day,and seven days of therapy,which can treat hypokalimeia caused from various kinds of reasons.
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A comparison of effectiveness of chemo-immunotherapy (CIT) using LAK/CD3AK 1-2 weeks after TACE in 74 patients with no surgical indication and TACE alone in 41 patients with moderately advanced HCC was carried out. The rates of remission between CIT group and TACE alone group were 72.4% and 40.4%(P
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Objective To evaluate the efficiency of different interventional mode in treating primary hepatocellular carcinoma with decompensated liver cirrhosis.Methods 132 cases with hepatocellular carcinoma accompanied by decompensational liver cirrhosis were undertaken transcatheter arterial chemo-embolization(TACE,Group A,n=36),segmental transcatheter arterial chemo-embolization(S-TACE,Group B,n=54)and S-TACE + radiofrequency ablation(RFA) + percutaneous ethanol injection(PEI)(multi-interventional therapy,Group C,n=42).Univariate analysis and multivariate COX proportional hazard regression model were used to analyze the factors affecting the prognosis.Results All patients of A,B,C groups had been followed up for 3 months to 48 months,with median survival times of 4.1 months,9.4 months(P 50%) demonstrated as 8.3%,31.5%(P
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24 patients with chronic hepatitis B were treated with interleukin-2 activated human peripheral blood lymphocytes (IAPBL). 23 patients served as control. The results showed that HBeAg disappeared in 54.2% of IAPBL group, in comparison with 17.4% of the controls (P
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Fifteen patients with hepatocellular failure from viral hepatitis were treated with general combined therapy and transfusion" of homologous fetal hepatic cells (FLO for 36 times (group A). An additional 15 cases with hepatocellular failure from viral hepatitis were treated only with general combined therapy, as control (group B). Twelve cases of the group A were diagnosed by transcutaneous liver biopsy.The results showed that FLC suspension achieved satisfactory effects and those who received FLC rallied remarkably better than those who did not. The fatality rates of group A and B were 26.7% (4/15) and 60.0% (9/15) respectively. In group A after transfusion of FLC, the effects were mainly shown by the elevation of the prothrombin activity (elevated for 16.5% after 24 h and for 18.2% after 48 h in average), recovery from hepatic coma and improvement in the subjective symptoms and various hepatic function tests. In survivals of group A (11 cases), the serum bilirubin returned to normal more quickly than that of group B (5 cases), being 55.4?24.5 days and 119.7?54.9 days, respectively (P