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.

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.

Drug-induced liver injury:Is it somehow foreseeable?

The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes P-450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

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.

Drug-induced liver injury in hospitalized patients with notably elevated alanine aminotransferase

AIM： To identify the proportion, causes and the nature of drug-induced liver injury （DILI） in patients with no- tably elevated alanine aminotransferase （ALT）. METHODS： All the inpatients with ALT levels above 10 times upper limit of normal range （ULN） were ret- rospectively identified from a computerized clinical laboratory database at our hospital covering a 12-mo period. Relevant clinical information was obtained from medical records. Alternative causes of ALT eleva- tions were examined for each patient, including bili- ary abnormality, viral hepatitis, hemodynamic injury, malignancy, DILI or undetermined and other causes. All suspected DILI cases were causality assessed usingthe Council for International Organizations of Medical Sciences scale, and only the cases classified as highly probable, probable, or possible were diagnosed as DILI. Comments related to the diagnosis of DILI in the medical record and in the discharge letter for each case were also examined to evaluate DILI detection by the treating doctors. RESULTS： A total of 129 cases with ALT 〉 i0 ULN were identified. Hemodynamic injury （n = 46, 35.7%）, DILl （n = 25, 19.4%） and malignancy （n = 21, 16.3%） were the top three causes of liver injury. Peak ALT val- ues were lower in DILI patients than in patients with hemodynamic injury （14.5 5.6 ULN vs 32.5 ：I： 30.7 ULN, P = 0.001）. Among DILI patients, one （4%） case was classified as definite, 19 （76%） cases were clas- sified as probable and 5 （20%） as possible according to the ClOMS scale. A hepatocellular pattern was ob- served in 23 （92%） cases and mixed in 2 （8%）. The extent of severity of liver injury was mild in 21 （84%） patients and moderate in 4 （16%）. Before discharge, 10 （40%） patients were recovered and the other 15 （60%） were improved. The improved patients tended to have a higher peak ALT （808 ＋ 348 U/L vs 623 ＋ 118 U/L, P = 0.016） and shorter treatment duration before discharge （8 ＋ 6 d vs 28 ~ 12 d, P = 0.008） compared with the recovered patients. Twenty-two drugs and 6 herbs were found associated with DILl. Antibacterials were the most common agents causing DILI in 8 （32%） cases, followed by glucocorticoids in 6 （24%） cases. Twenty-four （96%） cases received treatment of DILl with at least one adjunctive drug. Agents for treatment of DILI included anti-inflammatory drugs （e.g., glycyr- rhizinate）, antioxidants （e.g., glutathione, ademetionine 1,4-butanedisulfonate and tiopronin）, polyene phospha- tidyl choline and herbal extracts （e.g., protoporphyrin disodium and silymarin）. Diagnosis of DILl was not mentioned in the discharge letter in 60% of the cases. Relative to prevalent cases and cases from wards of internal medicine, incident cases and cases from surgi- cal wards had a higher risk of missed diagnosis in dis- charge letter [odds ratio （OR） 32.7, 95%CI （2.8-374.1）,CONCLUSION： DILI is mostly caused by use of anti- bacterials and glucocorticoids, and constitutes about one fifth of hospitalized patients with ALT 〉 10 ULN. DILI is underdiagnosed frequently.

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.

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.

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.

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].

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.

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-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.

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

Protection of the liver against CCl_4-induced injury by intramuscular electrotransfer of a kallistatin-encoding plasmid

AIM:To investigate the effect of transgenic expression of kallistatin(Kal) on carbon tetrachloride(CCl 4)induced liver injury by intramuscular(im) electrotransfer of a Kal-encoding plasmid formulated with poly-Lglutamate(PLG).METHODS:The pKal plasmid encoding Kal gene was formulated with PLG and electrotransferred into mice skeletal muscle before the administration of CCl 4.The expression level of Kal was measured.The serum biomarker levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),malonyldialdehyde(MDA),and tumor necrosis factor(TNF)-α were monitored.The extent of CCl 4-induced liver injury was analyzed histopathologically.RESULTS:The transgene of Kal was sufficiently expressed after an im injection of plasmid formulated with PLG followed by electroporation.In the Kal gene-transferred mice,protection against CCl 4-induced liver injury was reflected by significantly decreased serum ALT,AST,MDA and TNF-α levels compared to those in control mice(P < 0.01 to 0.05 in a dose-dependent manner).Histological observations also revealed that hepatocyte necrosis,hemorrhage,vacuolar change and hydropic degeneration were apparent in mice after CCl 4 administration.In contrast,the damage was markedly attenuated in the Kal gene-transferred mice.The expression of hepatic fibrogenesis marker transforming growth factor-β1 was also reduced in the pKal transferred mice.CONCLUSION:Intramuscular electrotransfer of plasmid pKal which was formulated with PLG significantly alleviated the CCl 4-induced oxidative stress and inflammatory response,and reduced the liver damage in a mouse model.

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.

Antioxidant activity and hepatoprotective effect of 10 medicinal herbs on CCl4-induced liver injury in mice

BACKGROUND Many natural products confer health benefits against diverse diseases through their antioxidant activities.Carbon tetrachloride(CCl4)is often used in animal experiments to study the effects of substances on liver injury and the related mechanisms of action,among which oxidative stress is a major pathogenic factor.AIM To compare antioxidant and hepatoprotective activities of ten herbs and identify and quantify phytochemicals for the one with strongest hepatoprotection.METHODS The antioxidant activity of ten medicinal herbs was determined by both ferricreducing antioxidant power and Trolox equivalent antioxidant capacity assays.The total phenolic and flavonoid contents were determined by Folin–Ciocalteu method and aluminum chloride colorimetry,respectively.Their effects on CCl4-induced oxidative liver injury were evaluated and compared in a mouse model by administrating each water extract(0.15 g/mL,10 mL/kg)once per day for seven consecutive days and a dose of CCl4 solution in olive oil(8%,v/v,10 mL/kg).The herb with the strongest hepatoprotective performance was analyzed for the detailed bioactive components by using high-performance liquid chromatography-electrospray ionization source-ion trap tandem mass spectrometry.RESULTS The results revealed that all tested herbs attenuated CCl4-induced oxidative liver injury;each resulted in significant decreases in levels of serum alanine transaminase,aspartate transaminase,alkaline phosphatase,and triacylglycerols.In addition,most herbs restored hepatic superoxide dismutase and catalase activities,glutathione levels,and reduced malondialdehyde levels.Sanguisorba officinalis(S.officinalis)L.,Coptis chinensis Franch.,and Pueraria lobata(Willd.)Ohwi root were the three most effective herbs,and S.officinalis L.exhibited the strongest hepatoprotective effect.Nine active components were identified in S.officinalis L.Gallic acid and(+)-catechin were quantified(7.86±0.45 mg/g and 8.19±0.57 mg/g dried weight,respectively).Furthermore,the tested herbs displayed a range of in vitro antioxidant activities proportional to their phenolic content;the strongest activities were also found for S.officinalis L.CONCLUSION This study is of value to assist the selection of more effective natural products for direct consumption and the development of nutraceuticals or therapeutics to manage oxidative stress-related diseases.

Escitalopram-induced liver injury: A case report and review of literature

BACKGROUND Depression is a growing public health problem that affects over 350 million people globally and accounts for approximately 7.5%of healthy years lost due to disability.Escitalopram,one of the first-line medications for the treatment of depression,is a selective serotonin reuptake inhibitor and one of the most commonly prescribed antidepressant medications worldwide.Although thought to be generally safe and with minimal drug-drug interactions,we herein present an unusual case of cholestatic liver injury,likely secondary to escitalopram initiation.CASE SUMMARY A 56-year-old Chinese lady presented with fever and cholestatic liver injury two weeks after initiation of escitalopram for the treatment of psychotic depression.Physical examination was unremarkable.Further investigations,including a computed tomography scan of the abdomen and pelvis and tests for hepatitis A,B and C and for autoimmune liver disease were unyielding.Hence,a diagnosis of escitalopram-induced liver injury was made.Upon stopping escitalopram,repeat liver function tests showed downtrending liver enzymes with eventual normalization of serum aspartate aminotransferase and alanine aminotransferase one-week post-discharge.CONCLUSION Clinicians should be aware of the possibility of escitalopram-induced liver injury when initiating depressed patients on antidepressant treatment.This requires extra vigilance as most patients may remain asymptomatic.Measurement of liver function tests could be considered after initiation of antidepressant treatment,especially in patients with pre-existing liver disease.

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.

Japanese herbal medicine, Saiko-keishi-to, prevents gut ischemia/reperfusion-induced liver injury in rats via nitric oxide

AIM:To determine whether Saiko-keishi-to(TJ-10),a Japanese herbal medicine,could protect liver injury induced by gut ischemia/reperfusion(I/R),and to investigate the role of NO. METHODS:Male Wistar rats were exposed to 30-min gut isohemia followed by 60 min of reperfusion.Intravital microscopy was used to monitor leukocyte recruitment.Plasma tumor necrosis factor(TNF)levels and alanine aminotransferase (ALT)activities were measured.TJ-10 1 g/(kg.d)was intragastrically administered to rats for 7 d.A NO synthase inhibitor was administered. RESULTS:In control rats,gut I/R elicited increases in the number of stationary leukocytes,and plasma TNF levels and ALT activities were mitigated by pretreatment with TJ-10.Pretreatment with the NO synthase inhibitor diminished the protective effects of TJ-10 on leukostasis in the liver,and the increase of plasma TNF levels and ALT activities.Pretreatment with TJ-10 increased plasma nitrite/nitrate levels. CONCLUSION:TJ-10 attenuates the gut I/R-induced hepatic microvascular dysfunction and sequential hepatocellular injury via enhancement of NO production.