Recent advances in the diagnosis of drug-induced liver injury

Drug-induced liver injury(DILI)is a major problem in the United States,commonly leading to hospital admission.Diagnosing DILI is difficult as it is a diagnosis of exclusion requiring a temporal relationship between drug exposure and liver injury and a thorough work up for other causes.In addition,DILI has a very variable clinical and histologic presentation that can mimic many different etiologies of liver disease.Objective scoring systems can assess the probability that a drug caused the liver injury but liver biopsy findings are not part of the criteria used in these systems.This review will address some of the recent updates to the scoring systems and the role of liver biopsy in the diagnosis of DILI.

Association of Cytokines with Clinical Indicators in Patients with Drug-Induced Liver Injury

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical indicators.Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with DILI.Based on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),antiinfective drugs,and other drugs,patients were divided into five groups.Cytokines were measured by Luminex technology.Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed.Results 73 patients were enrolled.Age among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine group.Interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:P<0.001;TNF-α:P<0.001)and cardiovascular medicine(IL-6:P=0.020;TNF-α:P=0.001)were lower than those in NSAIDs group.There was a positive correlation between ALT(r=0.697,P=0.025),AST(r=0.721,P=0.019),and IL-6 in NSAIDs group.Conclusion Older age may be more prone to DILI.Patients with NSAIDs have more severe liver damage in early stages of DILI,TNF-αand IL-6 may partake the inflammatory process of DILI.

Efficacy of Jian’ganle(健肝乐) versus Hugan Pian(护肝片),Glucuronolactone and Reduced Glutathione in Prevention of Antituberculosis Drug-induced Liver Injury

Summary： Evidence-based medicine is advocated by WHO and adopted by developed countries for many years. In China, however, the selection of essential medicine and various medical insurance reimbursement schemes medicine is usually based on experts＇ experience of prescription practice which is under heavy critics resulting from the lack of related comparative efficacy and evidence-based research. The efficacy of Jian＇ganle in prevention of drug-induced liver injury （DILI） caused by antituberculotics was evaluated in this study by comparison with Hugan Pian, glucuronolactone and reduced glutathione. Evidence was provided for relevant sectors such as Ministry for Human Resources and Social Security of the People＇s Republic of China and National Health and Family Planning Commission of the Peo- ple＇s Republic of China to select and renew the Essential Medicine List （EML）, the new rural cooperative medical scheme in China （NRCMS） list or the reimbursement list of industrial injury insurance. A total of 189 patients with initial pulmonary tuberculosis were divided into four groups who took antituberculotics combined with Jian＇ganle, Hugan Pian, glucuronolactone and reduced glutathione respectively. Their liver function profile including alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, total bilirubin （TBIL）, direct bilirubin （DBIL）, total protein （TP）, albumin （A） and globulin （G） were detected at admission as baseline and after treatment. The Jian＇ganle group was compared with the three others by chi-square tests. In an aspect of maintaining bilirubin indexes normal, Jian＇ganle was more efficacious than glucuronolactone. And Jian＇ganle had a little more efficacy than reduced glutathione to maintain protein indexes normal as well. And the therapeutic regimen of antituberculotics combined with Jian＇ganle was the best in treating tuberculosis and preventing DILI at the same time. The study showed that among the four hepatinicas which demonstrated similar prevention of DILI caused by antituberculotics, Jian＇ganle has more advantages over the three others to some extent, which provides a reliable basis for health sectors to select and renew the EML, NRCMS List or the reimbursement list of industrial injury insurance.

A new prognostic model for drug-induced liver injury especially suitable for Chinese population

Drug-induced liver injury(DILI)is a rare side effect of drugs caused by all kinds of prescription or over-the-counter chemi-cals,biological agents,traditional Chinese medicine(TCM),natu-ral medicine(NM),health products,dietary supplements and their metabolites,and even excipients,which can lead to jaundice,liver failure,or even death.Although it is rare in term of single drug,the occurrence of DILI in all liver injuries is not low due to the wide range of drugs and foods involved.Moreover,there was an increasing trend of incidence of DILI since 2010 worldwide,with Asian regions showing the highest incidence[1].

Insights on drug and gene delivery systems in liver fibrosis

Complications of the liver are amongst the world’s worst diseases.Liver fibrosis is the first stage of liver problems,while cirrhosis is the last stage,which can lead to death.The creation of effective anti-fibrotic drug delivery methods appears critical due to the liver’s metabolic capacity for drugs and the presence of insurmountable physiological impediments in the way of targeting.Recent breakthroughs in anti-fibrotic agents have substantially assisted in fibrosis;nevertheless,the working mechanism of anti-fibrotic medications is not fully understood,and there is a need to design delivery systems that are well-understood and can aid in cirrhosis.Nanotechnology-based delivery systems are regarded to be effective but they have not been adequately researched for liver delivery.As a result,the capability of nanoparticles in hepatic delivery was explored.Another approach is targeted drug delivery,which can considerably improve efficacy if delivery systems are designed to target hepatic stellate cells(HSCs).We have addressed numerous delivery strategies that target HSCs,which can eventually aid in fibrosis.Recently genetics have proved to be useful,and methods for delivering genetic material to the target place have also been investigated where different techniques are depicted.To summarize,this review paper sheds light on themost recent breakthroughs in drug and gene-based nano and targeted delivery systems that have lately shown useful for the treatment of liver fibrosis and cirrhosis.

A Case of Infectious Mononucleosis Induced Jaundice Complicated by Possible Drug Induced Liver Injury (DILI)

In this case, a young female presented with non-specific features such as fever, sore throat, headache and fatigue. She went on to develop epigastric pain, darkening of urine and jaundice, with no resolution of prior symptoms. Physical and Laboratory tests confirmed the primary diagnosis of infectious mononucleosis, however, prior history of treatment with multiple drugs led to a diagnosis of DILI as a complication. Appropriate treatment with I.V. antibiotics, hepatoprotective agents, steroids as well as discontinuation of all potential hepatotoxic agents showed significant improvement in patients’ symptoms and overall condition.

Effectiveness of drug interventions in nonalcoholic fatty liver disease:A network meta-analysis

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is a major chronic liver disorder worldwide,and there is no established treatment for this disease.We conducted a network meta-analysis(NMA)to compare existing treatments,which include four classes of antidiabetic drugs,and examined the optimum treatments for NAFLD.AIM To compare the effectiveness of different treatments for NAFLD.METHODS An NMA was conducted using Stata 14.0(Corporation LLC,College Station,United States)and R(X643.6.3 version)in this study.Eligible randomized controlled trials(RCTs)were searched in the PubMed,Cochrane Library,Embase,Medline and Web of Science databases from database inception to April 2021.Two researchers independently screened the available studies in strict accordance with inclusion and exclusion criteria.The Cochrane Risk of Bias tool was used to evaluate the risk of bias of the included studies.The variables with and without dimensional differences were calculated as the standardized mean difference and weighted mean difference,respectively.An inconsistency model and“nodesplitting”technique were used to test for inconsistency.Funnel plots were used to evaluate publication bias.RESULTS Twenty-two eligible RCTs involving 1377 participants were eventually included in our analysis.Data were pooled using a random-effects model.Our NMA results revealed that glucagon-like peptide-1 receptor agonists(GLP-1RAs)were the most effective treatment,yielding improvements in hepatic fat content(HFC),alanine aminotransferase(ALT),aspartate aminotransferase(AST),serumγ-glutamyl transferase(GGT)and body weight[surface under the cumulative ranking curve(SUCRA)=99.6%,92.6%,82.8%,92.3%and 99.6%,respectively],while thiazolidinediones(TZDs)were the best intervention for reducing the NAFLD activity score(NAS;SUCRA=98.9%).In addition,moderate performance was observed for the sodium glucose cotransporter-2 inhibitors groups(SUCRA=25.1%,66.2%,63.5%,58.2%and 71.9%for HFC,ALT,AST,GGT and body weight,respectively).However,metformin performed poorly according to most indicators(SUCRA=54.5%,0.3%,19.5%,33.7%,57.7%and 44.3%for HFC,NAS,ALT,AST,GGT and body weight,respectively).CONCLUSION GLP-1RAs may be the optimum choice for most patients with NAFLD.However,TZDs are considered the most effective therapies in NAFLD patients with histological disease activity.

Current remarks and future directions on the interactions between metabolic dysfunction-associated fatty liver disease and COVID-19

During the outbreak of the coronavirus disease 2019(COVID-19)pandemic,particular interest rose regarding the interaction between metabolic dysfunctionassociated fatty liver disease(MAFLD)and the COVID-19 infection.Several studies highlighted the fact that individuals with MAFLD had higher probability of severe acute respiratory syndrome coronavirus 2 infection and more severe adverse clinical outcomes.One of the proposed mechanisms is the inflammatory response pathway,especially the one involving cytokines,such as interleukin 6,which appeared particularly elevated in those patients and was deemed responsible for additional insult to the already damaged liver.This should increase our vigilance in terms of early detection,close follow up and early treatment for individuals with MAFLD and COVID-19 infection.In the direction of early diagnosis,biomarkers such as cytokeratin-18 and scoring systems such as Fibrosis-4 index score are proposed.COVID-19 is a newly described entity,expected to be of concern for the years to come,and MAFLD is a condition with an ever-increasing impact.Delineating the interaction between these two entities should be brought into the focus of research.Reducing morbidity and mortality of patients with COVID-19 and MAFLD should be the ultimate objective,and the optimal way to achieve this is by designing evidence-based prevention and treatment policies.

Advancing immunosuppression in liver transplantation: A narrative review

Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation(LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solidorgan transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.

Drug-induced liver injury and COVID-19:Use of artificial intelligence and the updated Roussel Uclaf Causality Assessment Method in clinical practice

BACKGROUND Liver injury is a relevant condition in coronavirus disease 2019(COVID-19)inpatients.Pathophysiology varies from direct infection by virus,systemic inflammation or drug-induced adverse reaction(DILI).DILI detection and monitoring is clinically relevant,as it may contribute to poor prognosis,prolonged hospitalization and increase indirect healthcare costs.Artificial Intelligence(AI)applied in data mining of electronic medical records combining abnormal liver tests,keyword searching tools,and risk factors analysis is a relevant opportunity for early DILI detection by automated algorithms.AIM To describe DILI cases in COVID-19 inpatients detected from data mining in electronic medical records(EMR)using AI and the updated Roussel Uclaf Causality Assessment Method(RUCAM).METHODS The study was conducted in March 2021 in a hospital in southern Brazil.The NoHarm©system uses AI to support decision making in clinical pharmacy.Hospital admissions were 100523 during this period,of which 478 met the inclusion criteria.From these,290 inpatients were excluded due to alternative causes of liver injury and/or due to not having COVID-19.We manually reviewed the EMR of 188 patients for DILI investigation.Absence of clinical information excluded most eligible patients.The DILI assessment causality was possible via the updated RUCAM in 17 patients.RESULTS Mean patient age was 53 years(SD±18.37;range 22-83),most were male(70%),and admitted to the non-intensive care unit sector(65%).Liver injury pattern was mainly mixed,mean time to normalization of liver markers was 10 d,and mean length of hospitalization was 20.5 d(SD±16;range 7-70).Almost all patients recovered from DILI and one patient died of multiple organ failure.There were 31 suspected drugs with the following RUCAM score:Possible(n=24),probable(n=5),and unlikely(n=2).DILI agents in our study were ivermectin,bicalutamide,linezolid,azithromycin,ceftriaxone,amoxicillin-clavulanate,tocilizumab,piperacillin-tazobactam,and albendazole.Lack of essential clinical information excluded most patients.Although rare,DILI is a relevant clinical condition in COVID-19 patients and may contribute to poor prognostics.CONCLUSION The incidence of DILI in COVID-19 inpatients is rare and the absence of relevant clinical information on EMR may underestimate DILI rates.Prospects involve creation and validation of alerts for risk factors in all DILI patients based on RUCAM assessment causality,alterations of liver biomarkers and AI and machine learning.

Insights into skullcap herb-induced liver injury

This editorial addresses the growing concern of herb-induced liver injury(HILI),focusing on a unique case of Skullcap-induced HILI report.This editorial underscore the significant mortality rate linked to Skullcap-induced HILI,emphasizing the importance of vigilant monitoring and intervention.As herbal supplement usage rises,collaboration among clinicians and researchers is crucial to comprehend and address the complexities of HILI,particularly those involving Skullcap.

Effects of two novel sugar drug candidates on CYP450 isoforms in different sexed Chinese human liver microsome in vitro

The sex-based differences between the effects of two novel sugar-based drug candidates,a sulfated polymannuroguluronate(SPMG-911)and an acidic oligosaccharide sugar chain compound(AOSC-971),on the enzymes CYP 1A2,CYP2E1 and CYP3A4 of Chinese human liver microsome were investigated.The results showed that neither SPMG-911 nor AOSC-971 have any effect on CYP3A4,AOSC-971 induced the CYP 2E1 in men but have no effect on CYP1A2,SPMG-911 inhibit the CYP1A2 also in men but have no effect on CYP2E1.The results are useful for their safety evaluation,as well as for the prediction of inter-drug interactions associated with the two drugs.

Changes of Liver Microsomal Drug-metabolizing System and Lipoperoxidation Activity in Scalded Rats and the Effects of Silybin

The dynamic changes of liver microsomal drug-metabolizing system (MDMS) andlipoperoxidation were studied in scalded rats. The effects of treatment with vitamin E and silybinwere also evaluated. The results showeed that liver microsomal cytochrome P-450 content, and p-nitroanisole demethylase (P-NOD) and aniline hydroxylase (AH) activity decreased markedlypostburn. On the contrary, liver lipoperoxide and mierosomal lipoperoxidation increased significantlyafter scalding. Both the increase of liver lipoperoxide and mierosomal lipoperoxidation and the de-crease of MDMS activity were prevented by vitamin E and silybin treatments.

Effects of alprostadil combined with nucleoside antiviral drugs on liver function, liver fibrosis markers and serum inflammatory factors in patients with decompensated liver cirrhosis with HBV infection

Objective:To explore the Effects of alprostadil combined with nucleoside antiviral drugs on liver function, liver fibrosis markers and serum inflammatory factors in patients with decompensated liver cirrhosis with HBV infection.Methods: 136 patients with decompensated cirrhosis of HBV infection who were hospitalized in Linxi Hospital of Kailuan General Hospital, Tangshan Infectious Disease Hospital and North China University of Technology Hospital from January to February 2018, 2017 were selected. All patients were divided into control group and case group by random number table method, 68 cases in each group. The control group was treated with routine liver protection and antiviral therapy, while the case group was treated with alprostadil on the basis of the control group. The changes of liver function, liver fibrosis, liver and spleen imaging indexes, anti-virus related indexes and inflammatory factors were observed before and after treatment in the two groups.Results: The total effective rate of the case group was 97.06%, which was significantly higher than that of the control group (85.29%), and the difference was statistically significant. The ALT, AST, TBIL, LN, HA, PCIII, CIV, portal vein diameter, spleen vein diameter, spleen thickness, IL-6, hs-CRP, TNF-α and TGF-β1 were significantly lower in the case group than in the control group. ALB, HBV DNA conversion rate, HBsAg negative rate, and HBeAg negative rate were significantly higher than the control group, the difference was statistically significant. Conclusion: Alprostadil combined with nucleoside antiviral drugs can significantly improve the decompensation of HBV infection Liver function in patients with cirrhosis, reduce the degree of liver fibrosis, inhibit the production of serum inflammatory factors, and can effectively inhibit HBV replication, clinical efficacy is significant, with certain clinical application value.

Late Protective Effects of the Anticalmodulin Drug Fluphenazine on Carbon Tetrachloride-induced Liver Necrosis

Fluphenazine (FP) treatment (50mg/kg bw, ip in saline) 30 min before or 6 or 10 h after CCl4 administration (1 ml/kg ip in olive oil) significantly prevented the liver necrosis produced by the hepatotoxin at 24 h. FP had enhancing effects on the covalent binding of CCl4 reactive metabolites to cellular constituents and on CCl4 induced lipid peroaldation.FP lowered bOdy temperature of the CCl4-poisoned animals during the 24 h observation period. The obtained results are compatible but do not prove the hypothesis that calmodulin (CaM) had participation in late occurring events preceding necrosis. FP lowering action on body temperature, however, might also play a role in the effects of this drug on the onset of CCl4 induced liver necrosis. FP levels in liver tissue as determined by gas chromatography-mass spectrometry evidenced the presence of the drug in amounts suffi cient to inhibit CaM and that suggests that not all preventive effects of FP are due to its indirect actions on the central nervous system via decreased body temperature

Primary liver cancer organoids and their application to research and therapy

Primary liver cancer is a leading cause of death worldwide. To create advanced treatments for primary liver cancer, studies have utilized models such as 2D cell culture and in vivo animal models. Recent developments in cancer organoids have created the possibility for 3D in vitro cultures that recapitulates the cancer cell structure and operation as well as the tumor microenvironment (TME) . However, before organoids can be directly translated to clinical use, tissue processing and culture medium must be standardized with unified protocols to decrease variability in results. Herein, we present the wide variety of published methodologies used to derive liver cancer organoids from patient tumor tissues. Additionally, we summarize validation methodologies for organoids in terms of marker expression levels with immunohistochemistry as well as the presence of mutations and variants through RNA-sequencing. Primary liver cancer organoids have exciting applications allowing for faster drug testing at a larger scale. Primary liver cancer organoids also assisit in uncovering new mechanisms. Through the coculture of different immune cells and cancer organoids, organoids are now better able to recapitulate the liver cancer TME. In addition, it further aids in the investigation of drug development and drug resistance. Lastly, we posit that the usage of liver cancer organoids in animal models provides researchers a methodology to overcome the current limitations of culture systems.

基于livertox数据库的药物说明书乙型肝炎再激活风险警示标注情况调查分析

目的调查和分析996种药物HBV再激活(HBV reactivation,HBVr)在livertox数据库的记录情况与药品说明书中HBVr用药警示信息进行对比分析。方法统计livertox数据库中药物的HBVr提示信息,并与丁香园用药助手系统中收录的药品说明书HBVr用药警示信息标注进行对比。结果livertox数据库中共有47个药物和1类药物有HBVr风险信息提示并已在我国上市。其中糖皮质激素类药物和10个药物说明书并无HBVr风险信息提示,有2个药物部分说明书有提示,部分没有。结论药品生产企业及时修订药品说明,根据最新信息增加警示标语。临床医师及药师在临床使用中,需加强对病毒性感染患者的用药监护。

Non-steroidal anti-inflammatory drugs:What is the actual risk of liver damage?

Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs, which taken as a group, represents one of the most frequently prescribed around the world. Thus, not surprisingly NSAIDs, along with antiinfectious agents, list on the top for causes of DrugInduced Liver Injury (DILI). The incidence of liver disease induced by NSAIDs reported in clinical studies is fairly uniform ranging from 0.29/100 000 [95% confidence interval (CI): 0.17-051] to 9/100 000 (95% CI: 6-15). However, compared with these results, a higher risk of liver-related hospitalizations was reported (3-23 per 100 000 patients). NSAIDs exhibit a broad spectrum of liver damage ranging from asymptomatic, transient, hyper-transaminasemia to fulminant hepatic failure. However, under-reporting of asymptomatic, mild cases, as well as of those with transient liver-tests alteration, in conjunction with reports non-compliant with pharmacovigilance criteria to ascertain DILI and flawed epidemiological studies, jeopardize the chance to ascertain the actual risk of NSAIDs hepatotoxicity. Several NSAIDs, namely bromfenac, ibufenac and benoxaprofen, have been withdrawn from the market due to hepatotoxicity; others like nimesulide were never marketed in some countries and withdrawn in others. Indeed, the contro-versy concerning the actual risk of severe liver disease persists within NSAIDs research. The present work intends (1) to provide a critical analysis of the dissimilar results currently available in the literature concerning the epidemiology of NSAIDS hepatotoxicity; and (2) to review the risk of hepatotoxicity for each one of the most commonly employed compounds of the NSAIDs family, based on past and recently published data.

Glutamine:aprecursor of glutathione and its effect on liver

AIM To investigate the relationship between alanyl-glutamine (ALA-GLN) and glutathione (GSH) biosynthesis in hepatic protection.METHODS Twenty male Wistar rats were randomly divided into two groups: one receiving standard parenteral nutrition (STD) and the other supplemented with or without ALA-GLN for 7 days. The blood and liver tissue samples were examined after 5-fluorouracil (5-FU) was injected peritoneally.RESULTS The concentration measurements were significantly higher in ALA-GLN group than in STD group in serum GLN (687 μmol/ L±50 μmol/ L vs 505 μmol/ L±39 μmol/ L, P＜0.05), serum GSH (14 μmol/ L±5 μmol/ L vs 7 μmol/ L±3 μmol/ L, P＜0.01) and in liver GSH content (6.9 μmol/ g±2.5 μmol/ g vs 4.4 μmol/ g±1.6 μmol/ g liver tissue, P＜0.05). Rats in ALA-GLN group had lesser elevations in hepatic enzymes after 5-FU administration.CONCLUSION The supplemented nutrition ALA-GLN can protect the liver function through increasing the glutathione biosynthesis and preserving the glutathione stores in hepatic tissue.

drug-induced autoimmune liver disease:a diagnostic dilemma of an increasingly reported disease

The aetiology of autoimmune hepatitis(AIH) is uncer-tain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs.AIH usually develops in individuals with a genetic back-ground mainly consisting of some risk alleles of the major histocompatibility complex(HLA).Many drugs have been linked to AIH phenotypes,which sometimes persist after drug discontinuation,suggesting that they awaken latent autoimmunity.At least three clini-cal scenarios have been proposed that refers to drug- induced autoimmune liver disease(DIAILD):AIH with drug-induced liver injury(DILI); drug induced-AIH(DI-AIH); and immune mediated DILI(IM-DILI).In addi-tion,there are instances showing mixed features of DI-AIH and IM-DILI,as well as DILI cases with positive autoantibodies.Histologically distinguishing DILI from AIH remains a challenge.Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however,a detailed standard-ised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diag-nosis between both entities.Growing information on the relationship of drugs and AIH is being available,being drugs like statins and biologic agents more fre-quently involved in cases of DIAILD.In addition,there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepa-totoxicity.Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of