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La hepatotoxicidad inducida por medicamentos es un diagnóstico de descarte. Típicamente, se presenta en pacientes que desarrollan cambios clínicos y bioquímicos compatibles con hepatitis, pero relacionados con el inicio reciente de agentes farmacológicos, y que se resuelven tras el retiro de la noxa. Su desarrollo se ha descrito con el uso de algunos antibióticos, antituberculosos, estatinas, herbolarios y antiinflamatorios no esteroideos; sin embargo, hay pocos reportes de casos con el uso de anticonceptivos orales, en los cuales el surgimiento de mecanismos idiosincráticos puede llevar a la presentación de características clínicas como ictericia y anormalidades en los exámenes de laboratorio, como la elevación de las transaminasas. Esto requiere de estudios extensos para descartar otras patologías que pueden presentarse de esta forma, lo que representa un reto clínico. En este artículo se muestra el reporte de un caso de una paciente con antecedente de uso crónico de anticonceptivos implantables y que, tras el ajuste de la terapia con el inicio de anticonceptivos orales, desarrolla un episodio de elevación marcada de transaminasas e ictericia.
Drug-induced liver injury is a rule-out diagnosis. Typically, it occurs in patients who develop clinical and biochemical changes compatible with hepatitis, but related to a history of recent onset of pharmacological agents, and resolves after withdrawal of the noxious substances. Its development has been described with the use of some antibiotics, antituberculosis agents, statins, herbal and nonsteroidal anti inflammatory drugs; however, there are few reports of cases with the use of oral contraceptives, in which the appearance of idiosyncratic mechanisms can lead to the presentation of clinical features such as jaundice and laboratory tests abnormalities, like transaminase elevation, requiring extensive studies to rule out other pathologies that may have this clinical presentation, wich represents a clinical challenge. We present a case report of a patient who had chronic use of implantable contraceptives and who, after adjustment of therapy with the start of oral contraceptives, developed an episode of marked elevation of transaminases and jaundice.
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Tanto la lesión hepática inducida por drogas (DILI), así como la lesión hepática inducida por hierbas (HILI), son una preocupación creciente en la atención sanitaria contemporánea que plantea importantes desafíos clínicos debido a sus variadas etiologías, presentaciones clínicas y posibles resultados potencialmente mortales. Presentamos el caso de un paciente masculino de 38 años con antecedentes de cálculos renales que consultó por dolor lumbar y hematuria. Al ingreso presentó ictericia, hepatomegalia, dolor a la palpación en fosa ilíaca derecha y no tenía signos de hepatopatía crónica, con pruebas de función hepática anormales, que mostraron un patrón hepatocelular asociado con hiperbilirrubinemia. Se descartó obstrucción biliar, trombosis portal, hepatitis autoinmune y viral, con panel autoinmune negativo. El paciente refirió haber consumido un remedio herbario para los cálculos renales llamado "vino rompe cálculos (chancapiedra)", que se supone contiene Phyllanthus niruri, cinco días antes del inicio de los síntomas. Una biopsia hepática reveló hepatitis aguda con infiltrado inflamatorio mixto. Debido al empeoramiento de las pruebas de función hepática y la sospecha de DILI idiosincrásico, se inició un ensayo terapéutico con corticosteroides, que resultó en una mejoría clínica y del perfil hepático. La gravedad de este caso nos recuerda la necesidad de incrementar el seguimiento por parte de las autoridades reguladoras de medicamentos, implementar campañas educativas para los pacientes e informar a la comunidad sobre productos con alertas activas.
Both drug-induced liver injury (DILI) and herb-induced liver injury (HILI) are a growing concern in contemporary healthcare that poses significant clinical challenges due to their varied etiology, clinical presentations, and potential life-threatening outcomes. We present the case of a 38-year-old male patient with a history of kidney stones who consulted for low back pain and hematuria. On admission he presented with jaundice, hepatomegaly, pain on palpation in the right iliac fossa and no signs of chronic liver disease, with abnormal liver function tests, which showed a hepatocellular pattern associated with hyperbilirubinemia. Biliary obstruction, portal thrombosis, autoimmune and viral hepatitis were ruled out, with negative autoimmune panel. The patient reported consuming an herbal remedy for kidney stones called "stone-breaking wine (chancapiedra)", presumed to contain Phyllanthus niruri, five days before the onset of symptoms. A liver biopsy revealedacute hepatitis with mixed inflammatory infiltrate. Due to worsening liver function tests and suspicion of idiosyncratic DILI, a therapeutic trial with corticosteroids was initiated, which resulted in clinical and liver profile improvement. The severity of this case reminds us of the need to increase follow-up by drug regulatory authorities, implement educational campaigns for patients, and inform the community about products with active alerts.
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A 68-year-old male patient with malignant left lung tumor was treated with gefitinib(250 mg,po,qd)for 29 days.Liver function test results showed AST 310 U·L-1,ALT 493 U·L-1,AKP 100 U·L-1,TBil 18 μmol·L-1,GGT 60 U·L-1,INR 1.81.Several liver function indicators of the patient showed abnormal,which was consistent with the clinical manifestations of moderate liver injury.The liver function index of the patient improved after the doctor adopted the suggestion of clinical pharmacists to protect the liver.Clinical pharmacists made a comprehensive and dynamic assessment of the patient's condition,analyzed the correlation between the patient's liver injury and gefitinib,and judged that the patient's liver injury was likely caused by gefitinib.Clinical pharmacists analyzed the drug use of a blind trial patient,proposed the follow-up treatment plan,and discussed the blind trial drugs,which provided references for clinical safe and rational drug use and had important reference significance.
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An elderly female melanoma patient who experienced severe liver injury after treatment with pembrolizumab and axitinib,which improved with glucocorticoid therapy.Through medication analysis and adverse reaction scale evaluated,it was considered that severe liver injury was more closely related to the immune checkpoint inhibitor,pembrolizumab.After a comprehensive analysis of the relationship between liver injury and immunotherapy,as well as the benefits and risks of immunotherapy for patients,immunotherapy was rechallenged 40 days after discontinuation of pembrolizumab.Restarting treatment with pembrolizumab after immune-mediated hepatitis poses a risk of recurrence of hepatotoxicity.After reviewing related literature,it had been found that the incidence of severe hepatotoxicity caused by rechallenging treatment was low,and the overall safety was controllable.Pembrolizumab had brought therapeutic benefits to patients,with no further immune-mediated liver injury of 5 cycles medication.This case can provide a reference for rechallenging immunotherapy after immune-mediated hepatitis.
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AIM:To study the expression of glucose transporters(GLUTs)and silent information regulators(SIRTs/sirtuins)in the liver of diabetic rats and human hepatocytes(LO2 cells)treated with high glucose.METHODS:(1)Twenty male SD rats were randomly divided into normal control(NC)group and diabetes mellitus(DM)group.The rats in DM group were given single intraperitoneal injection of streptozotocin(STZ,60 mg/kg)to establish the DM model,while the rats in NC group were intraperitoneally injected with equal volume of solvent once.Fasting blood glucose(FBG)and body mass were measured every 2 weeks.After 12 weeks of rearing,the blood and liver tissues of the rats were ob-tained after anesthesia with 1%sodium pentobarbitone,the biochemical indicators of blood were detected,and the liver in-dex was calculated.Hematoxylin-eosin(HE)staining and periodic acid-Schiff(PAS)staining were used to observe liver histopathological changes.Lipid accumulation in liver tissues was detected by oil red O staining.The expression levels of GLUTs and SIRTs family member proteins were detected in rat liver tissues.(2)The LO2 cells were treated with different concentrations of glucose for 48 h.The viability of the cells in each group was measured by CCK-8 assay,and Western blot was used to detected the protein expression levels of GLUTs and SIRTs in the cells.RESULTS:(1)Compared with NC group,the rats in DM group were depressed,lost weight,and the FBG and liver index were significantly increased(P＜0.05).The results of HE staining showed that the hepatic sinuses were dilatated and congested near the central vein in DM rats,and mild edema and scattered infiltration of inflammatory cells were found in liver cells.The results of oil red O staining showed the red fat droplets were diffusely scattered within liver cells in DM group.The results of PAS staining showed that there were numerous diffuse light purple circular droplets in the cytoplasm of the liver cells in the central ve-nous area of the DM rats.Western blot showed that the protein levels of GLUTs were higher and the protein levels of SIRTs were lower than those in NC group(P＜0.01).(2)The results of CCK-8 assay showed that the viability of LO2 cells was increased in 50 mmol/L glucose group(P＜0.01),without significant difference in 75,100 and 125 mmol/L glucose groups(all P＞0.05),and decreased in 150,175 and 200 mmol/L glucose groups(all P＜0.01).Later,150 mmol/L glu-cose was used as the high-glucose intervention condition.Western blot showed that the protein levels of GLUTs and SIRTs in LO2 cells under high glucose intervention were consistented with the results in animal experiments.CONCLUSION:High concentration of glucose can cause liver damage in SD rats and reduce the viability of human hepatocytes(LO2 cells).It can also increase the expression of GLUTs and decrease the expression of SIRTs in rat liver tissues and LO2 cells.Therefore,GLUTs and SIRTs family members may be the target proteins of diabetes-induced liver injury.
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Objective:To observe the effect of astragalus polysaccharides on liver injury in mice with viral hepatitis,and to investigate whether it can regulate the expression of nucleotide-binding oligomerization domain 1(NOD1)/receptor-interacting protein 2(RIP2)/nuclear factor-κB(NF-κB)immune inflammation mediated by signaling pathway plays a protective role in liver.Methods:Sixty female C3H/HeJ mice were divided into modeling group(50 mice)and normal group(10 mice)using a random number table.The mouse model of viral hepatitis was established by intraperitoneal injection of mouse hepatitis virus type 3(MHV-3)in the modeling group.After the successful modeling was confirmed,the surviving mice were divided into thymus peptide group(10 μg),astragalus polysaccharide low,medium and high dose groups(100,200,400 mg/kg astragalus polysaccharide lyophilized in 1 ml/100 g body weight saline)and model group by random number table.Model group and normal group were given the same amount of normal saline intraperitoneal injection,each group was given once a day for 1 month.Results:The model was confirmed by HE staining of liver tis-sue and detection of viral plaque.Compared with the normal group,the liver index,serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL)and tumor necrosis factor-α(TNF-α),IL-1β and IL-8,viral plaques in liver tissue,NOD1,RIP2 and NF-κB p65 expressions and p-NF-κB p65 level in the model group increased(P<0.05),and the liver tissue showed severe pathological changes.Compared with the model group,the liver indexes,serum ALT,AST,TBIL and TNF-α,IL-1β and IL-8,viral plaques in liver tissue,NOD1,RIP2 and NF-κB p65 expressions and p-NF-κB p65 level in the thymosin group and astragalus polysaccharide each 3-dose groups decreased(P<0.05),and the pathological changes of liver tissue were alleviated.The effect of astragalus polysaccharide was dose-dependent,and there were no significant differences in these indexes between thymosin group and astragalus polysaccharide medium dose group(P>0.05).Conclusion:Astragalus polysaccharides can improve the liver function of mice with viral hepatitis,reduce the inflammatory response and pathological changes of liver tissue,reduce the level of virus,specu-late and inhibit NOD1/RIP2/NF-κB pathway and down-regulate NOD1,RIP2 and NF-κB p65 expressions,inhibit p-NF-κB p65 level,and high dose of astragalus polysaccharide has the best effect,which is better than thymosin-α1.
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Objective To investigate the modeling elements of various types of animal models for acute liver injury,and to provide references and suggestions to establish and evaluate animal models of acute liver injury(ALI).Methods The animal experimental literature of ALI from 2002 to 2022 was searched in the databases of the China Knowledge Network,WanFang,Chongqing Vip(VIP),Chinese Medical Journal Full Text Data(Yiigle),and PubMed.The animal species,positive control drugs,modeling method,modeling drugs,and drug administration of the animal models of ALI in the literature were summarized.The result were analyzed using Excel,SPSS Modeler 18.0,and Cytoscape 3.8.2.Results A total of 896 articles were included in the databases.The most used animal models for ALI were male KM mice.The modeling method were mainly chemical liver injury,alcoholic liver injury,drug-related liver injury,and immune liver injury.①The corresponding main modeling method were intraperitoneal injection of 10 mL/kg of 0.1％CC14 in vegetable oil at 24 h before experiments,②gavage of 12.0 mL/kg of 50.0％～56.0％ethanol at 16 h before experiments,③intraperitoneal injection of 300 mg/kg APAP at 24 h before experiments,④tail vein injection of 20 mg/kg Con A at 8 h before experiments.Evaluation of the models was based on liver pathological indexes as the gold standard combined with biochemical indexes of serum ALT,AST,and SOD and MDA contents and activities in liver tissue homogenate as direct indicators.Conclusions Because the causes of ALI vary in clinical practice,the preparation of animal models of ALI should be based on the specific study content and characteristics,and the corresponding modeling method should be selected.
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Objective To explore the mechanism of hydroxyl safflower flavin A(HSYA)in the treatment of sepsis-induced liver injury by using metabolomics and network pharmacology.Methods A total of 50 male C57BL/6 mice were randomly divided into sham-operation group(10 mice),sepsis group(20 mice)and HSYA group(20 mice).Cecal ligation and puncture was conducted to establish the sepsis-induced liver injury mouse model.The mice in HSYA group were subcutaneously injected with HSYA after 2 hours of modeling.The content of serum inflammatory factors and liver function were detected,and the pathological changes of liver tissue were observed with HE staining,UPLC-Q-TOF-MS metabolomics was used to analyze liver tissue,screening for differential metabolites using multivariate statistical methods,network pharmacology was used to predict potential targets for HSYA treatment of sepsis-induced liver injury,and conduct GO and KEGG pathway enrichment analysis on potential targets,Metabo Analyst 5.0 database was used to match differential metabolites and potential targets between the model group and HSYA group,a targets metabolite-metabolism pathway network was constructed.AutoDock Vina software was used to perform molecular docking between HSYA and core genes,and finally RT-qPCR was used to verify the expression of core genes.Results HSYA can reduce the contents of IL-6,IL-1β and TNF-α in serum,restore liver function,and alleviate the morphological alternation in liver induced by sepsis.A total of 26 differential metabolites identified by metabolomics were screened out,including flufenamic acid,cryptolepine,opthalmic acid,fenpropathrin etc.,which were mainly involved in 5 metabolic pathways such as biosynthesis of unsaturated fatty acids and alpha-linolenic acid metabolism.Network pharmacology identified 81 potential targets,2 735 items enriched in GO and 124 signaling pathways enriched in KEGG;a total of 5 differential metabolites were matched for joint analysis,corresponding to 14 targets including IL1B,STAT3,PTGS2,TP53,etc.,involved in the regulation of metabolic disorders in sepsis-induced liver injury by HSYA.Molecular docking results showed that HSYA had good binding activity to IL1B,STAT3,PTGS2 and TP53 targets.RT-qPCR results showed that HSYA could inhibit the expressions of IL1B,STAT3 and PTGS2 in liver tissue.Conclusions HSYA may inhibit the release of inflammatory cytokines,maintain metabolic homeostasis,and alleviate sepsis-induced liver injury through modulating the expressions of IL1B,STAT3,and PTGS2.
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Objective To investigate the mechanism of Yes-associated protein 1(YAP1)ameliorating aristolochic acid 1(AAI)-induced liver injury in mice based on untargeted metabolomics techniques.Methods There were 83-week-old male hepatocyte-specific Yap1 gene knockout mice(genotyped as Yap1Flox/Flox,Albumin-Cre,aka.Yap1LKO)were randomly selected as the Yap1LKO+AAI group,and 8 Yap1Flox control mice as the Yap1Flox+AAI group.Both groups were injected intraperitoneally with AAI at a dose of 2.5 mg·kg-1·d-1 for 14 consecutive days.Genotypes were identified by tail PCR;serum alanine transaminase(ALT)and aspartate transaminase(AST)activities were determined by microplate assay;histopathological changes of liver tissue were observed by HE staining;and the protein expression of YAP1 in liver tissue was determined by immunohistochemistry.The untargeted metabolomics approach was used to analyze the liver tissue differential metabolites,and the samples were analyzed by ultra performance liquid chromatography-quadrupole-electrostatic field orbit trap high-resolution mass spectrometry,and the differential metabolites were screened by principal component analysis(PCA),Partial least square-discriminant analysis(PLS-DA),and orthogonal partial least squares-discriminant analysis(OPLS-DA);using HMDB database and METLIN database to identify metabolites,and the pathway enrichment of differential metabolites was analyzed by KEGG database.Results(1)After 14 days of AAI induction,the increase of body mass in Yap1LKO mice was lower than that in Yap1Flox mice,but there was no statistical significance(P＞0.05).On day 14,compared with the Yap1Flox+AAI group,the serum ALT and AST enzyme activities in the Yap1LKO+AAI group of mice were significantly increased(P＜0.05),and the histopathological damage of the liver was significantly aggravated.The livers of the Yap1Flox mice had a positive protein expression of YAP1,whereas the Yap1LKO mice did not have a positive protein expression of YAP1.(2)A total of 139 differential metabolites with significant changes(VIP＞1 and P＜0.05)were screened by metabonomic analysis;compared with Yap1LKO+ AAI group,62 liver metabolites in Yap1Flox+AAI group were up-regulated,including choline,taurine,hypotaurine,α-linolenic acid,eleostearic acid,chenodeoxycholic acid and so on.Seventy-seven metabolites were down-regulated including glycerophosphocholine,L-phosphatidylcholine,L-glutamine,L-serine,L-glutathione,5-methionine,phenylalanine,glucose 6-phosphate,lactic acid,uric acid glycosides,etc..KEGG-enriched pathways were mainly choline metabolism,glycerophospholipid metabolism,insulin resistance,glutathione metabolism,etc..Conclusion Hepatocyte-specific Yap1 gene knockout exacerbated AAI-induced liver injury in mice,and YAP1 was involved in the regulation of choline metabolism and glycerophospholipid metabolism through the up-regulation of unsaturated fatty acids,such as choline and taurine,which ameliorated AAI-induced liver injury in mice.
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ObjectiveTo investigate the effect of linalool against acute liver injury induced by aflatoxin B1（AFB1） in rats and explore its protective mechanism. MethodTwenty male SPF SD rats were randomly divided into three groups： Control （n=6）， AFB1 （n=7）， and linalool （n=7） groups. Linalool solution （200 mg·kg-1） was administered preventatively for 14 days， while the control and AFB1 groups intragastrically received an equivalent volume of double distilled water. After preventative administration of linalool， AFB1 solution （1 mg·kg-1， dissolved in saline） was intraperitoneally injected for two consecutive days to induce acute liver injury in rats. Samples were collected and processed 14 days after model establishment. Pathological changes in liver tissue of rats were observed using Hematoxylin-eosin（HE） staining and Masson staining. Biochemical detection was performed to measure the levels of alanine transaminase（ALT）， aspartate transaminase（AST）， γ-glutamyl transferase（GGT）， lactate dehydrogenase（LDH）， alkaline phosphatase（ALP）， total bilirubin（TBil）， direct bilirubin（DBil）， indirect bilirubin（IBil）， malondialdehyde（MDA）， superoxidedismutase（SOD）， catalase（CAT） ， glutathione（GSH）， Fe3+， and Fe2+ in the liver tissue. Western blot was adopted to assess protein expression levels of nuclear factor-erythroid 2-related factor 2（Nrf2） and heme oxygenase-1（HO-1）. Molecular docking was performed to verify the binding between linalool and key proteins of the Nrf2/HO-1 signaling pathway. Molecular dynamics techniques were used to confirm the stability and affinity of linalool binding with key proteins of the Nrf2/HO-1 signaling pathway. ResultPathological results showed that compared to that in the AFB1 group， the liver structure in the linalool group tended to be normal， with a significant decrease in blue collagen fibers. The linalool group exhibited significantly reduced levels of ALT， AST， GGT， LDH， ALP， TBil， DBil， and IBil （P<0.01）， Fe3+ and Fe2+ content， and oxidative stress marker MDA （P<0.01）. The levels of antioxidants SOD， CAT， and GSH significantly increased （P<0.01）. Molecular docking showed a molecular docking energy between linalool and Nrf2 and HO-1 targets of -5.495 6 and -5.199 4 kcal·mol-1（1 cal≈4.186 J）， respectively. Molecular dynamics results indicated strong affinity in the binding of linalool with Nrf2 and HO-1. Western blot revealed a significant increase in Nrf2 protein expression （P<0.05） and a decrease in HO-1 protein expression （P<0.01） in the linalool group. ConclusionLinalool may protect against AFB1-induced acute liver injury by modulating the Nrf2/HO-1 ferroptosis signaling pathway to inhibit liver cell ferroptosis and regulate hepatic oxidative stress levels.
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Objective @#To investigate the changes of lipid biomarkers and lipid metabolic pathways related to liver injury in BTBR ob/ob mice with type 2 diabetes mellitus by biochemical and metabolomics methods．@*Methods @# 16 BTBR wild-type (WT) mice (WT group) and 14 BTBR ob/ob obese mice (ob / ob group) at 7 weeks of age were selected and fed in SPF environment until 20 weeks of age．Liver injury was compared between the two groups : The activities of mitochondrial respiratory enzyme complex in liver tissue were detected by high-resolution respirators，and the lipid metabolomic analysis of liver tissue samples in the two groups of mice was performed by ultra-perform- ance liquid chromatography-quadrupole time-of-flight mass spectrometry，mainly detecting endogenous metabolites. Principal component analysis (PCA) ，orthogonal partial least squares discriminant analysis ( OPLS-DA) and other models were used to screen potential biomarkers，and the metabolic pathway analysis of the identified metabolites was performed by MetaboAnalyst 5. 0 . @*Results @#Compared with the WT group，the ob / ob group had significantly increased body weight，fasting blood glucose ，serum levels of aspartate aminotransferase ( AST) ，alanine amin- otransferase (ALT) ，low-density lipoprotein (LDL-C) and cholesterol ( CHO) (P＜0. 01) ．Liver hematoxylin-eo- sin staining (HE) staining showed that the mice in ob / ob group had structural disorder of liver lobules，swelling of liver cells ，a large number of fat vacuoles in cells ，diffuse distribution and loose cytoplasm． Oil red O staining showed that there was a large amount of lipid deposition in the hepatocytes ofob/ob mice．The high resolution spi- rometer showed that the ob/ob mice had mitochondrial oxidative phosphorylation disorder and the activity of complex Ⅳ decreased．Lipid metabolomic analysis showed that the lipid metabolic profile of ob/ob mice changed，and the metabolic pathways involved mainly included glycerophospholipid metabolism，glycosylphosphatidylinositol ( GPI) anchor biosynthesis，triglyceride metabolism，linoleic acid metabolism，α-linolenic acid metabolism and arachidon- ic acid metabolism．@*Conclusion @#The liver injury of ob / ob group mice may be related to the disorder of lipid me- tabolism，in which the disorder of glycerophospholipid metabolism is the most critical metabolic pathway.
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Objectives@#This study aimed to determine the effectiveness of N-acetylcysteine (NAC) in reversal of liver enzyme abnormalities among pediatric patients with dengue induced liver injury.@*Materials and Methods@#The preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P 2020) declaration was used to create this systematic review. The study population included children (<18 years old) diagnosed with dengue-associated Liver Injury and given NAC. The outcome of interest was full recovery. A search was performed in PubMed/MEDLINE, EMBASE, Google Scholar, HERDIN PLUS, WPRIM, clinicaltrials.gov, and Cochrane databases on March 2023. The New Castle-Ottawa Quality Assessment Scale was adapted for risk of bias assessment for cohort studies.@*Results@#Three case series and one pre-post cohort study published from 2013 to 2022 were included. The studies were of acceptable quality. In two studies with overall 10 pediatric patients given NAC for dengue-related ALF, all recovered without adverse events. In one study with 4 patients given NAC, half survived with their liver function tests returning to normal values. Finally, in one comparative study, the durations of time before the liver function tests returned to normal levels, and the mortality rates between those treated with and without N-acetyl cysteine were not significantly different. All studies reported no occurrence of adverse drug reaction related to NAC. @*Conclusion@#This systematic review shows limited evidence on the effectiveness of NAC in the reversal of liver enzymes among pediatric patients because of the low incidence of dengue induced liver injury seen in observational studies. Given that NAC is reported by all four studies to be accessible, effective, and with no attributable adverse events, its use can be considered. However, clinicians must still be cautioned given the limited available evidence.
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ObjectiveTo determine the scores of patients with a confirmed diagnosis of drug-induced liver injury （DILI） using Roussel Uclaf Causality Assessment Method （RUCAM）， Maria ＆ Victorino assessment scale， and Revised Electronic Causality Assessment Method （RECAM）， to compare the accuracy of the three scales in diagnosis， and to investigate their clinical significance in the diagnosis of DILI. MethodsA total of 98 patients with a confirmed diagnosis of DILI who were hospitalized in Peking University First Hospital from January 2011 to December 2022 were enrolled， with liver biopsy results supporting DILI and a clear history of medication. Clinical data were collected from all subjects， and the above causality assessment scales were used for scoring. The chi-square test was used to analyze the diagnostic accuracy of the causality assessment scales， and the weighted kappa coefficient was used to analyze the consistency between the three scales. ResultsFor all patients with DILI enrolled， RECAM had the highest accuracy， with a significant difference compared with RUCAM （χ2=5.667，P=0.017）. RUCAM and RECAM had moderate consistency in diagnosis （κw=0.469）， while RECAM and Maria ＆ Victorino scale had poor consistency （κw=0.156）. For the patients with acute DILI， RECAM， RUCAM， and Maria ＆ Victorino scales had a diagnostic inconsistency rate of 3.7%， 11.1%， and 42.6%， respectively； for the patients with hepatocellular type DILI， the three scales of a diagnostic inconsistency rate of 8.9%， 21.4%， and 62.5%， respectively； for the patients with cholestasis type or mixed type DILI， the three scales of a diagnostic inconsistency rate of 10.0%， 22.5%， and 47.5%， respectively. ConclusionThe use of RECAM and RUCAM scales in acute DILI can improve diagnostic rate， and for hepatocellular type DILI and DILI with the clinical manifestation of cholestasis （cholestasis type DILI and mixed type DILI）， the use of RECAM and RUCAM scales can also improve diagnostic rate. The selection of causality assessment scales with a relatively high accuracy based on the course and clinical classification of the disease may help to further improve clinical diagnostic rate.
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Drug-induced autoimmune-like hepatitis （DI-ALH） is a special clinical phenotype of drug-induced liver injury and has similar clinical features and laboratory test results to autoimmune hepatitis， and it is often difficult to distinguish them through liver biopsy. Therefore， correct differential diagnosis DI-ALH and autoimmune hepatitis is a crucial and difficult point in clinical practice. This article analyzes the research advances in the pathogenesis， clinical features， diagnosis and treatment， and prognosis of DI-ALH， in order to provide ideas for the diagnosis and treatment of such diseases among clinicians.
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Caveolin-1 （CAV1） is a structural protein of caveolae on the plasma membrane and is an important regulatory factor for liver function. CAV1 regulates hepatic lipid deposition， lipid and glucose metabolism， mitochondrial function， and hepatocyte proliferation through various molecular pathways. Therefore， CAV1 plays a crucial role in maintaining liver physiology during the metabolic regulatory processes such as hepatic steatosis and hepatocyte proliferation. Furthermore， CAV1 is also involved in the development and progression of different types of liver injury， hepatitis， and liver cirrhosis. This article reviews the role of CAV1 in liver-related diseases and its mechanism in the regulation of liver macrophages， so as to provide a theoretical basis for targeting CAV1 in the treatment of liver-related diseases.
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ObjectiveTo observe the microbial changes in Wistar rats with liver injury caused by the Dictamni Cortex-Flavescens Sophora by high-throughput sequencing technology and investigate the potential mechanism of liver injury caused by the Dictamni Cortex-Flavescens Sophora. MethodFemale Wistar rats were randomly divided into four groups： normal group， as well as low-dose， medium-dose， and high-dose groups of traditional Chinese medicine （TCM）. The rats were gavaged with the Dictamni Cortex-Flavescens Sophora in different doses （4.125， 8.25， 16.5 g·kg-1 of raw drug respectively） for 28 days， and the general condition was recorded. The liver-body weight ratio was calculated， and the biochemical indexes of serum were observed. The Hematoxylin-eosin （HE） staining was used to observe pathological changes in the liver， and 16S rDNA high-throughput sequencing was utilized to detect fecal microbial changes in rats. ResultCompared with the normal group， Dictamni Cortex-Flavescens Sophora increased the liver weights and liver-body weight ratios of Wistar rats. The difference in liver weight between the medium-dose and high-dose groups of TCM was statistically significant （P<0.05）， and the liver-body weight ratios of the low-dose， medium-dose， and high-dose groups of TCM were all statistically significant （P<0.05）. Compared with the normal group， serum albumin and cholesterol levels increased in the medium-dose and high-dose groups of TCM （P<0.05）. The histopathology of the liver in the medium-dose and high-dose groups of TCM showed tiny vacuole-like changes. Compared with the normal group， there were obvious intestinal flora disorders after administration of Dictamni Cortex-Flavescens Sophora， and alpha diversity increased in the medium-dose and high-dose groups of TCM. The principal coordinates analysis showed that species increasingly deviated from the normal group as the administered dose increased. Compared with the normal group， the proportion of Firmicutes and Bacteroidota decreased after the drug administration， and the genus level of Parasutterella， Romboutsia， Turicibacter， Allobaculum， and Dubosiella increased. The genus level of Lachnospiraceae_NK4A136_group， Blautia， Erysipelatoclostridium， Muribaculum， and Ruminococcus_gnavus_group decreased. The correlation analysis showed that Parasutterella， Romboutsia， Turicibacter， Allobaculum， and Dubosiella were positively correlated with serum cholesterol and liver-body weight ratio， and lanchnospiraceae_NK4A136_group， Blautia， Muribaculum， Erysipelatoclostridium， and Ruminococcus_gnavus_group were negatively associated with serum cholesterol and liver-body weight ratio. ConclusionThe liver injury caused by Dictamni Cortex-Flavescens Sophora is manifested as a lipid metabolism disorder， and the mechanism is related to the increase in lipid metabolism-related microorganisms.
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ObjectiveTo investigate whether paeonol exerts a protective effect on mice with alcoholic liver injury by regulating the takeda G-protein-coupled receptor 5 （TGR5）/protein kinase A （PKA）/cAMP response binding element （CREB） signaling pathway mediated by Eubacterium. MethodC57BL/6 mice were randomly divided into five groups： normal group， model group， paeonol group （480 mg·kg-1）， antibiotic group （Abs group）， and antibiotic + paeonol group. Lieber-DeCarli liquid was used to feed C57BL/6 mice on the second day of modeling for 10 days. The blood lipids， liver function， inflammatory factors， and oxidative stress levels in mice were measured. Hematoxylin-eosin staining （HE） and oil red O staining were used to observe the morphological changes and fat accumulation in liver tissue. 16S rDNA sequencing was used to detect the diversity of intestinal microbiota in the blank， model， and paeanol groups. Western blot was used to detect the effect of paeonol on the expression levels of protein related to the signaling pathway of atresia band protein 1 （ZO-1）， Claudin-1， and TGR5/PKA/CREB in mouse ileal tissue. ResultCompared with those in the blank group， the blood lipids， liver function， oxidative stress levels， and the expression of inflammatory factors in the model group increased （P<0.01）， and the liver fat vacuoles were obvious. The ileal mucosa was seriously damaged， and the protein contents of ZO-1， Claudin-1， and TGR5/PKA/CREB in the ileal tissue decreased significantly （P<0.01）. The intestinal microbiota changed， and the proteobacteria phylum increased significantly. The ratio of Bacteroidetes to Firmicutes decreased. The relative abundance of Dubosiella newyorkensis， Lactobacillus， Bifidobacterium， and other genera decreased， while the relative abundance of Escherichia-Shigella， Morganella， Providencia， and Proteus increased significantly. Compared with the model group， paeonol significantly reduced the blood lipids， liver function， oxidative stress levels， and expression of inflammatory factors in mice with alcohol diet-induced liver injury （P<0.05）， decreased liver fat vacuoles， improved and restored the ileal intestinal barrier， and restored the normal structure of hepatocytes and ileal cells. The intestinal microbiota disorder caused by alcohol was improved， and the relative abundance of beneficial bacteria such as Eubacterium spp. was increased. The protein expression levels of ZO-1， Claudin-1， and TGR5/PKA/CREB in ileal tissue were increased （P<0.05）. ConclusionPaeonol has a protective effect on alcoholic liver injury in mice， and the mechanism of action is achieved by regulating the Eubacterium-mediated TGR5/PKA/CREB signaling pathway to ensure anti-inflammatory effect and improve the intestinal barrier.
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Objective To analyze the effect and molecular mechanism of phellodendron amurense in the treatment of liver injury based on network pharmacology,and to verify the relevant prediction targets and the protective effect of phellodendron amurense extract-Phellodendron amurense polysaccharide on immune liver injury through mice.Methods TCMSP and Swiss target prediction databases were used to retrieve and screen phellodendron amurenses active components and action targets,and then obtain disease-related targets on GeneCards and OMIM websites,and take compounds and disease intersection targets for protein interaction.Analysis,GO biological function and KEGG signaling pathway enrichment analysis,followed by molecular docking of compounds and key target proteins,and finally established a mouse liver injury model induced by Daodou protein A(Con A)to explore the mechanism of phellodendron amurense extract in the treatment of liver injury.Results 37 active ingredients were screened.The key targets for their treatment were tumor necrosis factor α(TNF-α),serine/threonine protein kinase 1(AKT1),signal transduction and transcription activation factor 3(STAT3),epidermal growth factor receptor(EGFR)anditin.Enzyme 3(CASP3)and other enrichment analysis showed that phellodendron amurense might play a protective role in protecting the liver through molecular mechanisms such as positive regulation of MAPK cas-cade reaction,oxidative stress response and regulatory PI3K-Akt signaling pathway,lipid and atherosclerosis.Ani-mal experiments had found that the gastric treatment of phellodendron amurense polysaccharide could improve the activity of superoxide dismutase(SOD)and catalase(CAT)in liver tissue,reduce the levels of serum alkaline phosphatase(ALP),aspartate aminotransferase(AST)and malonaldehyde(MDA)in liver tissue,and regulate serum inflammatory factor while the expression of intercitin(IL)-6,IL-1 β,tumor necrosis factor α(TNF-α),ac-tivated the expression of transforming growth factor β1(TGF-β1),and reduced TNF-α mRNA expression in liver tissue.Conclusion Phellodendron amurense can intervene in lipid and atherosclerosis pathways by acting on tar-gets such as TNF-α,AKT1,STAT3,EGFR and CASP3 to reduce oxidative stress and inflammatory reactions and achieve liver protection.
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative method for various hematological diseases. With the optimization of transplantation technology, the clinical application of allo-HSCT is more and more mature. Post-transplant liver injury is one of the common postoperative complications, which seriously affects the quality of life and long-term survival of patients. The causes of liver injury after allo-HSCT can be divided into non-infectious and infectious factors, which show similar clinical manifestations and different treatment principles. Timely diagnosis of post-transplant liver injury and the identification of the disease cause will be beneficial for early prevention or targeted treatment, thereby improving patients' prognosis. This review focuses on the etiology, clinical features, and treatment options of liver injury after allo-HSCT, aiming to deepen the understanding of hematologists on liver injury after allo-HSCT.
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Objective To construct a machine learning prediction model for postoperative liver injury in patients with non-liver surgery based on preoperative and intraoperative medication indicators.Methods A case-control study was conducted on 315 patients with liver injury after non-liver surgery selected from the databases developed by 3 large general hospitals from January 2014 to September 2022.With the positive/negative ratio of 1 ∶3,928 cases in corresponding period with non-liver surgery and without liver injury were randomly matched as negative control cases.These 1243 patients were randomly divided into the modeling group(n=869)and the validation group(n=374)in a ratio of 7∶3 using the R language setting code.Preoperative clinical indicators(basic information,medical history,relevant scale score,surgical information and results of laboratory tests)and intraoperative medication were used to construct the prediction model for liver injury after non-liver surgery based on 4 machine learning algorithms,k-nearest neighbor(KNN),support vector machine linear(SVM),logic regression(LR)and extreme gradient boosting(XGBoost).In the validation group,receiver operating characteristic(ROC)curve,precision-recall curve(P-R),decision curve analysis(DCA)curve,Kappa value,sensitivity,specificity,Brier score,and F1 score were applied to evaluate the efficacy of model.Results The model established by 4 machine learning algorithms to predict postoperative liver injury after non-liver surgery was optimal using the XGBoost algorithm.The area under the receiver operating characteristic curve(AUROC)was 0.916(95%CI:0.883～0.949),area under the precision-recall curve(AUPRC)was 0.841,Brier score was 0.097,and sensitivity and specificity was 78.95%and 87.10%,respectively.Conclusion The postoperative liver injury prediction model for non-liver surgery based on the XGBoost algorithm has effective prediction for the occurrence of postoperative liver injury.