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.

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.

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.

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.

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.

Antituberculosis Drug-Induced Liver Injury: An Ignored Fact, Assessment of Frequency, Patterns, Severity and Risk Factors

Background/Aims: Antituberculosis drug-induced liver injury (TB DILI) is a frequent medical problem in Pakistan. Critical understanding of various aspects of TB DILI is not only important to manage liver injury but may also prevent unnecessary discontinuation of antituberculosis treatment. The study is aimed to determine the frequency, types, severity and patterns of TB DILI. Study further evaluates various risk factors of TB DILI. Materials and Methods: This is a prospective cohort study of two seventy-eight patients with the diagnosis of tuberculosis, where patients were followed during tuberculosis treatment. TB DILI was defined in accordance to international DILI expert working group. Results: Out of two seventy eight-patients, ninety-five (34.14%) had TB DILI. The most common pattern of TB DILI was hepatocellular (63.15%) followed by mixed (23.15%) and Cholestatic (13.68%). Most of the patients had mild DILI (43.15%) followed by moderate (30.52%), severe (20.01%) and very severe (5.26%). Age > 35 years, concomitant hepatotoxic drugs, extrapulmonary TB and malnutrition are important risk factors for TB DILI. Conclusion: All patterns of TB DILI with varying severity were present. Age > 35 years, malnutrition, extrapulmonary TB and concomitant use of hepatotoxic drugs were risk factors for TB DILI.

Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment

Causality assessment of suspected drug induced liver injury(DILI) and herb induced liver injury(HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences(CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved. 2014 Baishideng Publishing Group Co., Limited. All

Dissecting the molecular pathophysiology of drug-induced liver injury

Drug-induced liver injury(DILI) has become a major topic in the field of Hepatology and Gastroenterology. DILI can be clinically divided into three phenotypes: hepatocytic, cholestatic and mixed. Although the clinical manifestations of DILI are variable and the pathogenesis complicated, recent insights using improved preclinical models, have allowed a better understanding of the mechanisms that trigger liver damage. In this review, we will discuss the pathophysiological mechanisms underlying DILI. The toxicity of the drug eventually induces hepatocellular damage through multiple molecular pathways, including direct hepatic toxicity and innate and adaptive immune responses. Drugs or their metabolites, such as the common analgesic, acetaminophen, can cause direct hepatic toxicity through accumulation of reactive oxygen species and mitochondrial dysfunction. The innate and adaptive immune responses play also a very important role in the occurrence of idiosyncratic DILI. Furthermore, we examine common forms of hepatocyte death and their association with the activation of specific signaling pathways.

Pyrrolidine dithiocarbamate alleviates the anti-tuberculosis drug-induced liver injury through JAK2/STAT3 signaling pathway:An experimental study

Objective:To study the effect of pyrrolidine dithiocarbamate(PDTC) on the anti-tuberculosis drug-induced liver injury and the molecular mechanism. Methods:Clean male SD rats were selected as experimental animals and randomly divided into normal group,model group,PDTC group and AG490 group. Animal model of anti-tuberculosis drug-induced liver injury was established by intragastric administration isoniazid + rifampicin. PDTC group received intraperitoneal injection of PDTC,and AG490 group received intraperitoneal injection of AG490. Twenty-eight days after intervention,the rats were executed,and the liver injury indexes,inflammation indexes and oxidative stress indexes in serum as well as JAK2/STAT3 expression,liver injury indexes,inflammation indexes and oxidative stress indexes in liver tissue were determined. Results:p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissue as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of model group were significantly higher than those of normal group while p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissu as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of PDTC group and AG490 group were significantly lower than those of model group. Conclusions:PDTC can inhibit the inflammation and oxidative stress mediated by JAK2/STAT3 signaling pathway to alleviate the anti-tuberculosis drug-induced liver injury.

Clinical characteristics of drug-induced liver injury and primary biliary cirrhosis

AIM To summarize and compare the clinical characteristics of drug-induced liver injury(DILI) and primary biliary cirrhosis(PBC).METHODS A total of 124 patients with DILI and 116 patients with PBC treated at Shengjing Hospital Affiliated to China Medical University from 2005 to 2013 were included. Demographic data(sex and age),biochemical indexes(total protein,albumin,alanine aminotransferase,aspartate aminotransferase,total bilirubin,direct bilirubin,indirect bilirubin,alkaline phosphatase,and gamma glutamyltransferase),immunological indexes [immunoglobulin(Ig) A,Ig G,Ig M,antinuclear antibody,anti-smooth muscle antibody,anti-mitochondrial antibody,and anti-mitochondrial antibodies] and pathological findings were compared in PBC patients,untyped DILI patients and patients with different types of DILI(hepatocellular type,cholestatic type and mixed type). RESULTS There were significant differences in age and gender distribution between DILI patients and PBC patients. Biochemical indexes(except ALB),immunological indexes,positive rates of autoantibodies(except SMA),and number of cases of patients with different ANA titers(except the group at a titer of 1:10000)significantly differed between DILI patients and PBC patients. Biochemical indexes,immunological indexes,and positive rate of autoantibodies were not quite similar in different types of DILI. PBC was histologically characterized mainly by edematous degeneration of hepatocytes(n = 30),inflammatory cell infiltration around bile ducts(n = 29),and atypical hyperplasia of small bile ducts(n = 28). DILI manifested mainly as fatty degeneration of hepatocytes(n = 15) and spotty necrosis or loss of hepatocytes(n = 14).CONCLUSION Although DILI and PBC share some similar laboratory tests(biochemical and immunological indexes) and pathological findings,they also show some distinct characteristics,which are helpful to the differential diagnosis of the two diseases.

Hepatobiliary manifestations in inflammatory bowel disease: The gut,the drugs and the liver

Abnormal liver biochemical tests are present in up to30%of patients with inflammatory bowel disease(IBD),and therefore become a diagnostic challenge.Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn’s disease and ulcerative colitis(UC),and typically do not correlate with intestinal activity.Primary sclerosing cholangitis(PSC)is the most common hepatobiliary manifestation of IBD,and is more prevalent in UC.Approximately 5%of patients with UC develop PSC,with the prevalence reaching up to 90%.Cholangiocarcinoma and colon cancer risks are increased in these patients.Less common disorders include autoimmune hepatitis/PSC overlap syndrome,IgG4-associated cholangiopathy,primary biliary cirrhosis,hepatic amyloidosis,granulomatous hepatitis,cholelithiasis,portal vein thrombosis,liver abscess,and non-alcoholic fatty liver disease.Hepatitis B reactivation during immunosuppressive therapy is a major concern,with screening and vaccination being recommended in serologically negative cases for patients with IBD.Reactivation prophylaxis with entecavir or tenofovir for 6to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen(HBsAg)positive,independently from viral load.HBsAg negative and anti-HBc positive patients,with or without anti-HBs,should be closely monitored,measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy,and should be treated if the viral load increases.On the other hand,immunosuppressive therapy does not seem to promote reactivation of hepatitis C,and hepatitis C antiviral treatment does not influence IBD natural history either.Most of the drugs used for IBD treatment may induce hepatotoxicity,although the incidence of serious adverse events is low.Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant.Methotrexaterelated hepatotoxicity has been described in 14%of patients with IBD,in a dose-dependent manner.Liver biopsy is not routinely recommended.Biologics-related hepatotoxicity is rare,but has been shown most frequently in patients treated with infliximab.Thiopurines have been associated with veno-occlusive disease,regenerative nodular hyperplasia,and liver peliosis.Routine liver biochemical tests are recommended,especially during the first month of treatment.All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement.Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.

Ayurvedic drug induced liver injury

Drug induced liver injury is responsible for 50% of acute liver failure in developed countries. Ayurvedic and homeopathic medicine have been linked to liver injury. This case describes the first documented case of Punarnava mandur and Kanchnar guggulu causing drug induced liver injury. Drug induced liver injury may be difficult to diagnosis, but use of multi-modalities tools including the ACG algorithms, causative assessment scales, histological findings, and imaging, is recommended. Advanced imaging, such as magnetic resonance cholangiopancreatography, may possibly have a greater role than previously reported in literature.

Systematic Review and Meta-Analysis of Hugan Tablets (护肝片) in the Treatment of Drug-Induced Liver Injury

Objective:To systematically evaluate the efficacy and safety of Hugan Tablets(护肝片)in the treatment of drug-induced liver injury.Methods:Totally seven Chinese and English databases,including CNKI,Wanfang,VIP,CBM,PubMed,EMbase,Web of Science were searched for randomized controlled trials(RCTs)of Hugan Tablets(护肝片)for the treatment of drug-induced liver injury,which were published from the date of establishment to April 20,2019.The meta-analysis software RevMan 5.3 software and Excel were used to build a database into combine and analyze the studies that met the standards and to draw a forest plot.Results:Forty five RCTs were included with 7478 patients.The quality of included studies was uneven.Meta-analysis showed that the outcome index of liver injury rate was divided into seven subgroups.Hugan Tablets(护肝片)were used in the treatment of anti-tuberculosis drugs was superior to the conventional western medicine treatment group(RR=0.27,95%CI[0.22,0.33],P<0.00001).Which was also better than the without Hugan Tablets(护肝片)treatment group(RR=0.32,95%CI[0.20,0.52],P<0.00001).For the role of drug-induced liver injury in the treatment of type 2 diabetes,the Hugan Tablet+conventional treatment group is better than the conventional treatment group(RR=0.16,95%CI[0.03,0.88],P=0.03).The effect of drug-induced liver injury in the treatment of hypertension was superior to the conventional western medicine treatment group(RR=0.07,95%CI[0.03,0.14],P<0.00001).The effect of drug-induced liver injury during the treatment of hyperlipidemia was not statistically significant(RR=0.57,95%CI[0.33,1.00],P=0.05).There was no statistical difference between the two groups in the effect of drug-induced liver injury during the treatment of coronary heart disease(RR=0.09,95%CI[0.01,1.61],P=0.10).There was no significant difference between the two groups in the treatment of cerebral thrombosis for drug-induced liver injury(RR=0.11,95%CI[0.01,2.01],P=0.14).The effect of anti-hyperthyroidism on liver injury was better than that of conventional western medicine treatment group(RR=0.45,95%CI[0.25,0.82],P=0.009).Outcome index of total effective rate was divided into two subgroups.The effect of drug-induced liver injury caused by the type of drug was not mentioned was superior to the conventional western medicine treatment group(RR=0.78,95%CI[0.70,0.88],P<0.0001).There was no significant difference between the two groups in the liver injury caused by antipsychotic drugs(RR=0.97,95%CI[0.81,1.16],P=0.72).Conclusion:When used in the treatment of tuberculosis and psychiatric drug treatment,combineduse of Hugan Tablets(护肝片)can significantly reduce the incidence of drug-induced liver damage,and can significantly improve clinical symptoms caused by liver damage.In the treatment of hypertension,the addition of Hugan Tablets(护肝片)can significantly reduce the incidence of drug-induced liver injury,improving the safety of medication.In the treatment of drug-induced liver injury caused by which drug is not mentioned,Hugan Tablet has a therapeutic effect.Slight adverse reactions were reported,including rash,headache,palpitations,hypoglycemia,flushing,fatigue,nausea,bowel sounds,flatulence,diarrhea,and gastrointestinal discomfort.All studies reported minor adverse reactions that were well tolerated by patients and recovered without treatment after discontinuation.Oral administration of Hugan Tablets(护肝片)has positive effects on druginduced liver injury,but this conclusion still needs further evidences delete.It is necessary to adopt a larger sample,more design,and accord with the international standards to improve the quality of evidence.

Drug induced autoimmune hepatitis:An unfortunate case of herbal toxicity from Skullcap supplement:A case report

BACKGROUND The surge in traditional herbal dietary supplement(HDS)popularity has led to increased drug-induced liver injuries(DILI).Despite lacking evidence of efficacy and being prohibited from making medical claims,their acceptance has risen over sevenfold in the last two decades,with roughly 25%of United States(US)adults using these supplements monthly.An estimated 23000 emergency room visits annually in the US are linked to HDS side effects.NIH-funded research suggests HDS contribute to 7-20%of DILI cases,with similar trends in Europe—Spain reporting 2%and Iceland up to 16%.Patients with acute liver failure from HDS undergo liver transplantation more frequently than those from prescription medicines.Here we describe a case of drug-induced autoimmune hepatitis due to Skullcap supplements,this association appears to be the first documented instance in literature.CASE SUMMARY A middle-aged Caucasian woman,previously healthy,presented with sudden jaundice.Four months earlier,her liver enzymes were normal.She mentioned recent use of Skullcap mushroom supplements.Tests for chronic liver disease were negative.The first liver biopsy indicated severe resolving drug-induced liver injury.Despite treatment,she was readmitted due to worsening jaundice.Followup tests raised concerns about autoimmune hepatitis.A subsequent biopsy confirmed this diagnosis.The patient responded as expected to stopping the medication with improvement in liver enzymes.CONCLUSION This scenario highlights an uncommon instance of DILI caused by Skullcap supplements.It's crucial for hepatologists to recognize this connection due to the increasing prevalence of herbal supplements.

Immune-mediated liver injury following COVID-19 vaccination

Liver injury secondary to vaccination is a rare adverse event that has recently come under attention thanks to the continuous pharmacovigilance following the widespread implementation of coronavirus disease 2019(COVID-19)vaccination protocols.All three most widely distributed severe acute respiratory syndrome coronavirus 2 vaccine formulations,e.g.,BNT162b2,mRNA-1273,and ChAdOx1-S,can induce liver injury that may involve immune-mediated pathways and result in autoimmune hepatitis-like presentation that may require therapeutic intervention in the form of corticosteroid administration.Various mechanisms have been proposed in an attempt to highlight immune checkpoint inhibition and thus establish causality with vaccination.The autoimmune features of such a reaction also prompt an in-depth investigation of the newly employed vaccine technologies.Novel vaccine delivery platforms,e.g.,mRNA-containing lipid nanoparticles and adenoviral vectors,contribute to the inflammatory background that leads to an exaggerated immune response,while patterns of molecular mimicry between the spike(S)protein and prominent liver antigens may account for the autoimmune presentation.Immune mediators triggered by vaccination or vaccine ingredients per se,including autoreactive antibodies,cytokines,and cytotoxic T-cell populations,may inflict hepatocellular damage through wellestablished pathways.We aim to review available data associated with immunemediated liver injury associated with COVID-19 vaccination and elucidate potential mechanisms underlying its pathogenesis.

Herb-induced liver injury: Systematic review and meta-analysis

BACKGROUND The use of herbal supplements and alternative medicines has been increasing in the last decades.Despite popular belief that the consumption of natural products is harmless,herbs might cause injury to various organs,particularly to the liver,which is responsible for their metabolism in the form of herb-induced liver injury(HILI).AIM To identify herbal products associated with HILI and describe the type of lesion associated with each product.METHODS Studies were retrieved using Medical Subject Headings Descriptors combined with Boolean operators.Searches were run on the electronic databases Scopus,Web of Science,MEDLINE,BIREME,LILACS,Cochrane Library for Systematic Reviews,SciELO,Embase,and Opengray.eu.Languages were restricted to English,Spanish,and Portuguese.There was no date of publication restrictions.The reference lists of the studies retrieved were searched manually.To access causality,the Maria and Victorino System of Causality Assessment in Drug Induced Liver Injury was used.Simple descriptive analysis were used to summarize the results.RESULTS The search strategy retrieved 5918 references.In the final analysis,446 references were included,with a total of 936 cases reported.We found 79 types of herbs or herbal compounds related to HILI.He-Shou-Wu,Green tea extract,Herbalife,kava kava,Greater celandine,multiple herbs,germander,hydroxycut,skullcap,kratom,Gynura segetum,garcinia cambogia,ma huang,chaparral,senna,and aloe vera were the most common supplements with HILI reported.Most of these patients had complete clinical recovery(82.8%).However,liver transplantation was necessary for 6.6%of these cases.Also,chronic liver disease and death were observed in 1.5%and 10.4%of the cases,respectively.CONCLUSION HILI is normally associated with a good prognosis,once the implied product is withdrawn.Nevertheless,it is paramount to raise awareness in the medical and non-medical community of the risks of the indiscriminate use of herbal products.

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

Liver injury from direct oral anticoagulants

BACKGROUND Drug-induced liver injury(DILI)can be caused by any prescribed drug and is a significant reason for the withdrawal of newly launched drugs.Direct-acting oral anticoagulants(DOACs)are non-vitamin K-based antagonists recently introduced and increasingly used for various clinical conditions.A meta-analysis of 29 randomised controlled trials and 152116 patients reported no increased risk of DILI with DOACs.However,it is challenging to predict the risk factors for DILI in individual patients with exclusion of patients with pre-existing liver disease from these studies.AIM To determine the risk factors and outcomes of patients who developed DILI secondary to DOACs by systematic review and meta-summary of recent case reports and series.METHODS A systematic search was conducted on multiple databases including PubMed,Science Direct,Reference Citation Analysis,and Google Scholar.The search terms included“Acute Liver Failure”OR“Acute-On-Chronic Liver Failure”OR“Acute Chemical and Drug Induced Liver Injury”OR“Chronic Chemical and Drug Induced Liver Injury”AND“Factor Xa Inhibitors”OR“Dabigatran”OR“Rivaroxaban”OR“apixaban”OR“betrixaban”OR“edoxaban”OR“Otamixaban”.The results were filtered for literature published in English and on adult patients.Only case reports and case studies reporting cases of DILI secondary to DOACs were included.Data on demographics,comorbidities,medication history,laboratory investigations,imaging,histology,management,and outcomes were extracted.RESULTS A total of 15 studies(13 case reports and 2 case series)were included in the analysis,comprising 27 patients who developed DILI secondary to DOACs.Rivaroxaban was the most commonly implicated DOAC(n=20,74.1%).The mean time to onset of DILI was 40.6 d.The most common symptoms were jaundice(n=15,55.6%),malaise(n=9,33.3%),and vomiting(n=9,33.3%).Laboratory investigations showed elevated liver enzymes and bilirubin levels.Imaging studies and liver biopsies revealed features of acute hepatitis and cholestatic injury.Most patients had a favourable outcome,and only 1 patient(3.7%)died due to liver failure.CONCLUSION DOACs are increasingly used for various clinical conditions,and DILI secondary to DOACs is a rare but potentially serious complication.Prompt identification and cessation of the offending drug are crucial for the management of DILI.Most patients with DILI secondary to DOACs have a favourable outcome,but a small proportion may progress to liver failure and death.Further research,including post-marketing population-based studies,is needed to better understand the incidence and risk factors for DILI secondary to DOACs.

Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population

BACKGROUND Polygonum multiflorum is one of the leading causes of herb-induced liver injury in China.HLA-B*35:01 is reported to be a potential biomarker of Polygonum multiflorum-induced liver injury(PM-DILI).However,little is known about the relationship between single-nucleotide polymorphisms(SNPs) and PM-DILI.AIM To identify SNPs that indicate susceptibility to PM-DILI METHODS We conducted a systematic study enrolling 382 participants from four independent hospitals,including 73 PM-DILI patients,118 patients with other drug-induced liver injury(other-DILI) and 191 healthy controls.Whole-exome sequencing was performed for 8 PM-DILI patients and 8 healthy controls who were randomly selected from the above subjects.Nineteen SNPs that showed high frequencies in the 8 PM-DILI patients were selected as candidate SNPs and then screened in 65 PM-DILI patients,118 other-DILI patients and 183 healthy controls using the MassARRAY system.HLA-B high-resolution genotyping was performed for the 73 PM-DILI and 118 other-DILI patients.The Han-MHC database was selected as a population control for HLA-B analysis.P <6.25 x 103 after Bolferroni correction was considered significant.RESULTS The frequencies of rslll686806 in the HLA-A gene,rs1055348 in the HLA-B gene,and rs202047044 in the HLA-DRB1 gene were significantly higher in the PM-DILI group than in the control group [27.2% vs 11.6%,P=1.72×105,odds ratio(OR)=3.96,95% confidence interval(Cl):2.21-7.14;42.5% vs 8.6%,P=1.72×10-19 OR=13.62,95% CI:7.16-25.9;22.9% vs 8.1%,P=4.64×106,OR=4.1,95% CI:2.25-7.47].Only rs1055348 showed a significantly higher frequency in the PM-DILI group than in the other-DILI group(42.5% vs 13.6%,P=1.84×10-10,OR=10.06,95% Cl:5.06-20.0),which suggested that it is a specific risk factor for PM-DILI.rs1055348 may become a tag for HLA-B*35:01 with 100% sensitivity and 97.7% specificity in the PM-DILI group and 100% sensitivity and 98.1% specificity in the other-DILI group.Furthermore,HLA-B*35:01 was confirmed to be associated with PM-DILI with a frequency of 41.1% in the PM-DILI group compared with 11.9%(P=4.30×10-11,OR=11.11,95% CI:5.57-22.19) in the other-DILI group and 2.7%(P=6.22×10-166,OR=62.62,95% Cl:35.91-109.20) in the Han-MHC database.CONCLUSION rslll686806,rs1055348,and rs202047044 are associated with PM-DILI,of which,rs1055348 is specific to PM-DILI.As a tag for HLA-B*35:01,rs1055348 may become an alternative predictive biomarker of PM-DILI.

Atypical onset of bicalutamide-induced liver injury

Anti-androgen therapy is the leading treatment for advanced prostate cancer and is commonly used for neoadjuvant or adjuvant treatment. Bicalutamide is a non-steroidal anti-androgen, used during the initiation of androgen deprivation therapy along with a luteinizing hormone-releasing hormone agonist to reduce the symptoms of tumor-related flares in patients with advanced prostate cancer. As side effects, bicalutamide can cause fatigue, gynecomastia, and decreased libido through competitive androgen receptor blockade. Additionally, although not as common, drug-induced liver injury has also been reported. Herein, we report a case of hepatotoxicity secondary to bicalutamide use. Typically, bicalutamideinduced hepatotoxicity develops after a few days; however, in this case, hepatic injury occurred 5 mo after treatment initiation. Based on this rare case of delayed liver injury, we recommend careful monitoring of liver function throughout bicalutamide treatment for prostate cancer.