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 c...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.展开更多
Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced...Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced liver injury(ATB-DILI),and to explore its protective effect and mechanism on ATB-DILI,so as to provide experimental basis for the clinical application of Yigan capsule.Methods:Twenty-four rats were divided into two groups.Except for the blank group(n=6),the other 18 rats were given isoniazid(INH)+rifampicin(RFP)(50 mg/kg.d)for 4 weeks.Then 18 rats were randomly divided into three groups(model group,low dose group of Yigan capsule and high dose group of Yigan capsule)according to 6 rats in each group.The blank group and the model group were given 0.9%sodium chloride solution by intragastric administration.The low dose group of Yigan capsule was 0.468 g/kg,and the high dose group of Yigan capsule was 1.872 g/kg[1].After 4 weeks,the pathological changes of liver were observed by HE staining.The contents of ALT,AST,ALP,γ-GT and TBIL were detected.The expression of HMGB1,NF-κBp65 and RAGE protein was detected by IHC.The expression levels of HMGB1,NF-κBp65,RAGE,TNF-αand IL-1βwere detected by WB.Result:HE staining showed that the structure of the liver in the model group was disordered,the liver cells showed swelling and fusion,the number of inflammatory cells increased and accompanied by punctate necrosis,while the above pathological changes in each treatment group of Yigan capsule were significantly improved.The contents of ALT,AST,ALP,γ-GT and TBIL in the model group were higher than those in the blank group(P<0.05).The contents of ALT,AST,ALP,γ-GT and TBIL in each treatment group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of TNF-αand IL-1βin the model group were increased(P<0.05),and the expression levels of HMGB1,NF-κBp65 and RAGE were increased(P<0.05).Compared with the model group,the expression levels of TNF-αand IL-1βin each treatment group of Yigan capsule decreased(P<0.05),and the expression of HMGB1,NF-κBp65 and RAGE decreased(P<0.05).Conclusion:Yigan capsule may inhibit the secretion of inflammatory factors through HMGB1/RAGE/NF-κBp65 signaling pathway,thus protecting ATB-DILI.展开更多
Drug-induced liver injury(DILI)is caused by various drugs with complex pathogenesis,and diverse clinical and pathological phenotypes.Drugs damage the liver directly through drug hepatotoxicity,or indirectly through dr...Drug-induced liver injury(DILI)is caused by various drugs with complex pathogenesis,and diverse clinical and pathological phenotypes.Drugs damage the liver directly through drug hepatotoxicity,or indirectly through drug-mediated oxidative stress,immune injury and inflammatory insult,which eventually lead to hepatocyte necrosis.Recent studies have found that the composition,relative content and distribution of gut microbiota in patients and animal models of DILI have changed significantly.It has been confirmed that gut microbial dysbiosis brings about intestinal barrier destruction and microorganisms translocation,and the alteration of microbial metabolites may cause or aggravate DILI.In addition,antibiotics,probiotics,and fecal microbiota transplantation are all emerging as prospective therapeutic methods for DILI by regulating the gut microbiota.In this review,we discussed how the altered gut microbiota participates in DILI.展开更多
Drug-induced interstitial lung disease(DILD)is the most common pulmonary adverse event of anticancer drugs.In recent years,the incidence of anticancer DILD has gradually increased with the rapid development of novel a...Drug-induced interstitial lung disease(DILD)is the most common pulmonary adverse event of anticancer drugs.In recent years,the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents.Due to the diverse clinical manifestations and the lack of specific diagnostic criteria,DILD is difficult to diagnose and may even become fatal if not treated properly.Herein,a multidisciplinary group of experts from oncology,respiratory,imaging,pharmacology,pathology,and radiology departments in China has reached the“expert consensus on the diagnosis and treatment of anticancer DILD”after several rounds of a comprehensive investigation.This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening,diagnosis,and treatment of anticancer DILD.This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.展开更多
BACKGROUND Interleukin-17(IL-17)inhibitors are known to cause exacerbation or new onset of inflammatory bowel disease upon administration.However,few reports have described characteristic endoscopic and histopathologi...BACKGROUND Interleukin-17(IL-17)inhibitors are known to cause exacerbation or new onset of inflammatory bowel disease upon administration.However,few reports have described characteristic endoscopic and histopathologic findings,and no small intestinal lesions have been reported so far.CASE SUMMARY A woman in her 60s with psoriasis was administered ixekizumab(IXE),an anti-IL-17A antibody,for the treatment of psoriasis.Twenty months after commencing treatment,the patient visited our hospital because of persistent diarrhea.Blood tests performed at the time of the visit revealed severe inflammation,and colonoscopy revealed multiple round ulcers throughout the colon.A tissue biopsy of the ulcer revealed infiltration of inflammatory cells and granuloma-like findings in the submucosal layer.Capsule endoscopy revealed multiple jejunal erosions.After the withdrawal of IXE,the symptoms gradually improved,and ulcer reduction and scarring of the colon were endoscopically confirmed.CONCLUSION To the best of our knowledge,17 reports have documented IL-17 inhibitorinduced entero-colitis with endoscopic images,endoscopic findings,and pathological characteristics,including the present case.Nine of these cases showed diffuse loss of vascular pattern,coarse mucosa/ulcer formation in the left colon,and endoscopic findings similar to those of ulcerative colitis.In the remaining eight cases,discontinuous erosions and ulcerations from the terminal ileum to the rectum were seen,with endoscopic findings similar to those of Crohn’s disease.In this case,the findings were confirmed by capsule endoscopy,which has not been previously reported.展开更多
BACKGROUND A 70-year-old man with hepatitis C virus-related recurrent hepatocellular carcinoma was admitted for further diagnosis of a 1 cm iso-hyperechoic nodule in segment(S)5.CASE SUMMARY Gadolinium ethoxybenzyl di...BACKGROUND A 70-year-old man with hepatitis C virus-related recurrent hepatocellular carcinoma was admitted for further diagnosis of a 1 cm iso-hyperechoic nodule in segment(S)5.CASE SUMMARY Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging(EOB-MRI)revealed the nodule in S5 with a defect at the hepatobiliary phase,hyperintensity on diffusion weighted imaging(DWI)and hypointensity on apparent diffusion coefficient(ADC)map.Contrast-enhanced computed tomography revealed hypervascularity at the early phase,and delayed contrast-enhancement was observed at the late phase.Contrast-enhanced ultrasound(US)revealed incomplete defect at the late vascular phase.Inflammatory liver tumor,lymphoproliferative disease,intrahepatic cholangiocarcinoma(small duct type)and bile duct adenoma were suspected through the imaging studies.US guided biopsy,however,showed a noncaseating hepatic sarcoid-like epithelioid granuloma(HSEG),and histopathological analysis disclosed spindle shaped epithelioid cells harboring Langhans-type multinucleated giant cells.One month after admission,EOB-MRI signaled the disappearance of the defect at the hepatobiliary phase,of hyperintensity on DWI,of hypointensity on ADC map,and no stain at the early phase.CONCLUSION That the patient had received BNT162b2 messenger RNA(mRNA)coronavirus disease 2019 vaccination 3 mo before the occurrence of HSEG,and that its disappearance was confirmed 4 mo after mRNA vaccination suggested that the drug-induced sarcoidosis-like reaction(DISR)might be induced by the mRNA vaccination.Fortunately,rechallenge of drug-induced DISR with the third mRNA vaccination was not confirmed.展开更多
BACKGROUND Empirical use of potentially hepatotoxic drugs in the management of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection is considered as one of the major etiopathogenetic factors for liver ...BACKGROUND Empirical use of potentially hepatotoxic drugs in the management of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection is considered as one of the major etiopathogenetic factors for liver injury.Recent evidence has shown that an underlying genetic factor may also occur.Hence,it is important to understand the host genetics and iatrogenic-based mechanisms for liver dysfunction to make timely remedial measures.AIM To investigate drug-induced and genetic perspectives for the development of coronavirus disease 2019(COVID-19)-related liver injury.METHODS Reference Citation Analysis,PubMed,Google Scholar and China National Knowledge Infrastructure were searched by employing the relevant MeSH keywords and pertaining data of the duration,site and type of study,sample size with any subgroups and drug-induced liver injury outcome.Genetic aspects were extracted from the most current pertinent publications.RESULTS In all studies,the hepatic specific aminotransferase and other biochemical indices were more than their prescribed upper normal limit in COVID-19 patients and were found to be significantly related with the gravity of disease,hospital stay,number of COVID-19 treatment drugs and worse clinical outcomes.In addition,membrane bound O-acyltransferase domain containing 7 rs641738,rs11385942 G>GA at chromosome 3 gene cluster and rs657152 C>A at ABO blood locus was significantly associated with severity of livery injury in admitted SARS-CoV-2 patients.CONCLUSION Hepatic dysfunction in SARS-CoV-2 infection could be the result of individual drugs or due to drug-drug interactions and may be in a subset of patients with a geneticpropensity. Thus, serial estimation of hepatic indices in hospitalized SARS-CoV-2 patients shouldbe done to make timely corrective actions for iatrogenic causes to avoid clinical deterioration.Additional molecular and translational research is warranted in this regard.展开更多
Drug-induced autoimmune hepatitis(DIAIH)is a specific phenotype of druginduced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation.Drugs implicated in DIAIH inc...Drug-induced autoimmune hepatitis(DIAIH)is a specific phenotype of druginduced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation.Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline,non-steroidal anti-inflammatory drugs,statins as well as anti-tumor necrosis agents.The clinical features of druginduced liver injury are indistinguishable from idiopathic autoimmune hepatitis(AIH)as both may have positive AIH-related autoantibodies,elevated immunoglobulin G,as well as similar histopathological findings.In patients who show no clinical improvement,or there is progressive liver injury despite cessation of the suspected drug,a liver biopsy should be considered,whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH.Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury.A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper.In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature.Early identification and treatment often lead to a favorable outcome in DIAIH.展开更多
Background: The diagnosis of drug-induced autoimmune hepatitis(DIAIH) and its differentiation from idiopathic autoimmune hepatitis(AIH) is challenging. This study aimed to differentiate DIAIH from AIH by comparing the...Background: The diagnosis of drug-induced autoimmune hepatitis(DIAIH) and its differentiation from idiopathic autoimmune hepatitis(AIH) is challenging. This study aimed to differentiate DIAIH from AIH by comparing the biochemical changes, histological features, and frequencies of CD4~+Foxp3~+CD25+/-regulatory T cells(Tregs) in liver tissues or peripheral blood lymphocytes.Methods: A total of 15 DIAIH patients and 24 AIH patients who underwent liver biopsies at initial presentation were enrolled in this study. The liver histological changes were assessed by HE staining. The phenotypic recognition and distribution of CD4~+Foxp3~+CD25+/-Tregs in liver tissues were evaluated by single/double immunostains in serial sections. The CD4~+Foxp3~+CD25+/-Tregs in peripheral blood were analyzed by flow cytometry.Results: The median values of ALT and AST were 404.50 U/L and 454.10 U/L in DIAIH patients and309.50 U/L and 315.00 U/L in AIH patients, respectively. More importantly, for the first time we found that patients with DIAIH had higher levels of serum ALT and AST, more severe degree of lobular inflammation,higher frequencies of zone 3 necrosis and higher number of lobular CD4~+Foxp3~+CD25~-Tregs compared with AIH(P < 0.05). Furthermore, there were positive correlations in DIAIH between the degree of lobular inflammation and either the AST/ALT level or the number of lobular CD4~+Foxp3~+CD25~-Tregs(P < 0.05).However, the frequency of peripheral blood CD4~+Foxp3~+CD25+/-Tregs were not significantly different between DIAIH and AIH.Conclusions: The differences of ALT, AST and the number of lobular CD4~+Foxp3~+CD25~-Tregs between patients with DIAIH and those with AIH are clinically helpful in differentiating these two diseases in their early stage.展开更多
Drug-induced liver injury(DILI)is an uncommon event in clinical practice,which makes knowing its true incidence difficult.Prospective,retrospective and registry-based studies are the most important methods to obtain e...Drug-induced liver injury(DILI)is an uncommon event in clinical practice,which makes knowing its true incidence difficult.Prospective,retrospective and registry-based studies are the most important methods to obtain epidemiological data on DILI.Latin America(LA)has a historical lack of prospective studies on this topic.New definitions and the creation of hepatotoxicity registries have significantly improved the epidemiological understanding of hepatic drug reactions in several regions of the world.The Latin American DILI network,referred to as LATINDILI,has been created in 2011,and recently published its own DILI recommendations describing the most relevant issues on the management of hepatotoxicity in general,and those based on findings from our own LA experience in particular.Although most of the registries do not carry out population-based studies,they may provide important data related to the prevalence of DILI.The joint work among researchers and the corresponding health and regulatory authorities should be stimulated due to the high impact that hepatotoxicity represents for public health.展开更多
The spectrum of drug-induced liver injury （DILI） is both diverse and complex. The first step in diagnosis is a suspicion of DILl based on careful consideration of recent comprehensive reports on the disease. There a...The spectrum of drug-induced liver injury （DILI） is both diverse and complex. The first step in diagnosis is a suspicion of DILl based on careful consideration of recent comprehensive reports on the disease. There are some situations in which the suspicion of DILI is particularly strong. Exclusion of other possible etiologies according to the pattern of liver injury is essential for the diagnosis. In patients with suspected DILl, diagnostic scales, such as the Councils for International Organizations of Medical Sciences/ Roussel Uclaf Causality Assessment Method （CIOMS/RUCAM） scale, may be helpful for the final diagnosis. Early management of DILl involves prompt withdrawal of the drug suspected of being responsible, according to serum levels of alanine aminotransferase （ALT）, alkaline phosphatase （ALP）, and total bilirubin （T-Bil）. However, as DILI patients may show resolution of liver injury without discontinuation of the drug, it should be carefully evaluated whether the suspected drug should be discontinued immediately with adequate consideration of the importance of the medication.展开更多
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-4...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.展开更多
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...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.展开更多
AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treat...AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.展开更多
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-gr...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展开更多
Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosi...Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.展开更多
AIM: To analyze the outcome of patients with severe drug-induced liver disease (DILD) associated with jaundice classified as hepatocellular, cholestatic or mixed liver injury and to evaluate the validity of Hy’s rule...AIM: To analyze the outcome of patients with severe drug-induced liver disease (DILD) associated with jaundice classified as hepatocellular, cholestatic or mixed liver injury and to evaluate the validity of Hy’s rule and the most important predictors for outcome. METHODS: The Adverse Drug Reaction Advisory Committee was set up in 1997 in our hospital to identify all suspicions of DILD following a structured prospective report form. Liver damage was divided into hepatocellular, cholestatic, and mixed types according to laboratory and histologic criteria when available. Further evaluation of causality assessment was performed. RESULTS: From January 1997 to December 2004, 265 patients were diagnosed with DILD,and 140 (52.8%) of them were female. hepatocellular damage was the most common (72.1%), the incidence of death was 9.9% in patients with hepatocellular damage and 9.5% in patients with cholestatic/mixed damage (P < 0.05). There was no difference in age of dead and recovered patients. The proportion of females and males was similar in recovered and dead patients, no difference was observed in duration of treatment between the two groups. The serum total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and aspartate transaminase (AST) (P = 0.013) values were higher in dead patients than in recovered patients. Chinese herbal medicine was the most frequently prescribed, accounting for 24.2% of the whole series. However, antitubercular drugs (3.4%) were found to be the primary etiological factor for fetal DILD. Factors associated with the development of fulminanthepatic failure were hepatic encephalopathy (OR = 43.66, 95% CI = 8.47-224.95, P < 0.0001), ascite (OR = 28.48, 95% CI = 9.26-87.58, P < 0.0001), jaundice (OR = 11.43, 95% CI = 1.52-85.96, P = 0.003), alcohol abuse (OR = 3.83, 95% CI = 1.26-11.67, P = 0.035) and direct bilirubin (OR = 1.93, 95% CI = 1.25-2.58, P = 0.012). CONCLUSION: Death occurs in 9.8% of patients with DILD. Chinese herbal medicine stands out as the most common drug for DILD. While antitubercular drugs are found to be the primary etiological factor for fetal DILD, hepatic encephalopathy, ascites, jaundice, alcohol abuse and direct bilirubin levels are associated with the death of DILD patients.展开更多
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 ...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.展开更多
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 r...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.展开更多
With over 100000 hospital admissions per annum,acute pancreatitis remains the leading gastrointestinal cause of hospitalization in the United States and has farreaching impact well beyond.It has become increasingly re...With over 100000 hospital admissions per annum,acute pancreatitis remains the leading gastrointestinal cause of hospitalization in the United States and has farreaching impact well beyond.It has become increasingly recognized that druginduced pancreatitis(DIP),despite accounting for less than 3%of all cases,represents an important and growing though often inconspicuous cause of acute pancreatitis.Nevertheless,knowledge of DIP is often curtailed by the limited availability of evidence needed to implicate given agents,especially for nonprescription medications.Indeed,the majority of available data is derived from case reports,case series,or case control studies.Furthermore,the mechanism of injury and causality for many of these drugs remain elusive as a definitive correlation is generally not established(<10%of cases).Several classification systems have been proposed,but no single system has been widely adopted,and periodic updates are required in light of ongoing pharmacologic expansion.Moreover,infrequently prescribed medications or those available over-thecounter(including herbal and other alternative remedies)are often overlooked as a potential culprit of acute pancreatitis.Herein,we review the ever-increasing diversity of DIP and the potential mechanisms of injury with the goal of raising awareness regarding the nature and magnitude of this entity.We believe this manuscript will aid in increasing both primary and secondary prevention of DIP,thus ultimately facilitating more expedient diagnosis and a decrease in DIPrelated morbidity.展开更多
基金funded by The National Key Research and Development Program(2022YFC2603500,2022YFC2603505)Beijing Municipal Health Commission high-level public health technical personnel construction project,discipline leader-03-26+2 种基金Beijing Hospitals Authority Clinical medicine Development of special funding support(XMLX202127)The Digestive Medical Coordinated Development Center of Beijing Hospitals Authority(XXZ0302)The capital health research and development of special(2022-1-2172)。
文摘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.
基金Scientific Research Project of Heilongjiang Provincial Education Department(No.12531608)。
文摘Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced liver injury(ATB-DILI),and to explore its protective effect and mechanism on ATB-DILI,so as to provide experimental basis for the clinical application of Yigan capsule.Methods:Twenty-four rats were divided into two groups.Except for the blank group(n=6),the other 18 rats were given isoniazid(INH)+rifampicin(RFP)(50 mg/kg.d)for 4 weeks.Then 18 rats were randomly divided into three groups(model group,low dose group of Yigan capsule and high dose group of Yigan capsule)according to 6 rats in each group.The blank group and the model group were given 0.9%sodium chloride solution by intragastric administration.The low dose group of Yigan capsule was 0.468 g/kg,and the high dose group of Yigan capsule was 1.872 g/kg[1].After 4 weeks,the pathological changes of liver were observed by HE staining.The contents of ALT,AST,ALP,γ-GT and TBIL were detected.The expression of HMGB1,NF-κBp65 and RAGE protein was detected by IHC.The expression levels of HMGB1,NF-κBp65,RAGE,TNF-αand IL-1βwere detected by WB.Result:HE staining showed that the structure of the liver in the model group was disordered,the liver cells showed swelling and fusion,the number of inflammatory cells increased and accompanied by punctate necrosis,while the above pathological changes in each treatment group of Yigan capsule were significantly improved.The contents of ALT,AST,ALP,γ-GT and TBIL in the model group were higher than those in the blank group(P<0.05).The contents of ALT,AST,ALP,γ-GT and TBIL in each treatment group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of TNF-αand IL-1βin the model group were increased(P<0.05),and the expression levels of HMGB1,NF-κBp65 and RAGE were increased(P<0.05).Compared with the model group,the expression levels of TNF-αand IL-1βin each treatment group of Yigan capsule decreased(P<0.05),and the expression of HMGB1,NF-κBp65 and RAGE decreased(P<0.05).Conclusion:Yigan capsule may inhibit the secretion of inflammatory factors through HMGB1/RAGE/NF-κBp65 signaling pathway,thus protecting ATB-DILI.
基金This study was supported by grants from the National Natu-ral Science Foundation of China(82000561,81974078,81570530,81370550,81974062,81720108006)the Natural Science Founda-tion of Hubei Province(2019ACA1333)the Science Foundation of Union Hospital(2021xhyn005).
文摘Drug-induced liver injury(DILI)is caused by various drugs with complex pathogenesis,and diverse clinical and pathological phenotypes.Drugs damage the liver directly through drug hepatotoxicity,or indirectly through drug-mediated oxidative stress,immune injury and inflammatory insult,which eventually lead to hepatocyte necrosis.Recent studies have found that the composition,relative content and distribution of gut microbiota in patients and animal models of DILI have changed significantly.It has been confirmed that gut microbial dysbiosis brings about intestinal barrier destruction and microorganisms translocation,and the alteration of microbial metabolites may cause or aggravate DILI.In addition,antibiotics,probiotics,and fecal microbiota transplantation are all emerging as prospective therapeutic methods for DILI by regulating the gut microbiota.In this review,we discussed how the altered gut microbiota participates in DILI.
基金supported by grants from CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2021-I2M-1-014)and National Key R&D Program of China(No.2021YFC2500700).
文摘Drug-induced interstitial lung disease(DILD)is the most common pulmonary adverse event of anticancer drugs.In recent years,the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents.Due to the diverse clinical manifestations and the lack of specific diagnostic criteria,DILD is difficult to diagnose and may even become fatal if not treated properly.Herein,a multidisciplinary group of experts from oncology,respiratory,imaging,pharmacology,pathology,and radiology departments in China has reached the“expert consensus on the diagnosis and treatment of anticancer DILD”after several rounds of a comprehensive investigation.This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening,diagnosis,and treatment of anticancer DILD.This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.
文摘BACKGROUND Interleukin-17(IL-17)inhibitors are known to cause exacerbation or new onset of inflammatory bowel disease upon administration.However,few reports have described characteristic endoscopic and histopathologic findings,and no small intestinal lesions have been reported so far.CASE SUMMARY A woman in her 60s with psoriasis was administered ixekizumab(IXE),an anti-IL-17A antibody,for the treatment of psoriasis.Twenty months after commencing treatment,the patient visited our hospital because of persistent diarrhea.Blood tests performed at the time of the visit revealed severe inflammation,and colonoscopy revealed multiple round ulcers throughout the colon.A tissue biopsy of the ulcer revealed infiltration of inflammatory cells and granuloma-like findings in the submucosal layer.Capsule endoscopy revealed multiple jejunal erosions.After the withdrawal of IXE,the symptoms gradually improved,and ulcer reduction and scarring of the colon were endoscopically confirmed.CONCLUSION To the best of our knowledge,17 reports have documented IL-17 inhibitorinduced entero-colitis with endoscopic images,endoscopic findings,and pathological characteristics,including the present case.Nine of these cases showed diffuse loss of vascular pattern,coarse mucosa/ulcer formation in the left colon,and endoscopic findings similar to those of ulcerative colitis.In the remaining eight cases,discontinuous erosions and ulcerations from the terminal ileum to the rectum were seen,with endoscopic findings similar to those of Crohn’s disease.In this case,the findings were confirmed by capsule endoscopy,which has not been previously reported.
文摘BACKGROUND A 70-year-old man with hepatitis C virus-related recurrent hepatocellular carcinoma was admitted for further diagnosis of a 1 cm iso-hyperechoic nodule in segment(S)5.CASE SUMMARY Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging(EOB-MRI)revealed the nodule in S5 with a defect at the hepatobiliary phase,hyperintensity on diffusion weighted imaging(DWI)and hypointensity on apparent diffusion coefficient(ADC)map.Contrast-enhanced computed tomography revealed hypervascularity at the early phase,and delayed contrast-enhancement was observed at the late phase.Contrast-enhanced ultrasound(US)revealed incomplete defect at the late vascular phase.Inflammatory liver tumor,lymphoproliferative disease,intrahepatic cholangiocarcinoma(small duct type)and bile duct adenoma were suspected through the imaging studies.US guided biopsy,however,showed a noncaseating hepatic sarcoid-like epithelioid granuloma(HSEG),and histopathological analysis disclosed spindle shaped epithelioid cells harboring Langhans-type multinucleated giant cells.One month after admission,EOB-MRI signaled the disappearance of the defect at the hepatobiliary phase,of hyperintensity on DWI,of hypointensity on ADC map,and no stain at the early phase.CONCLUSION That the patient had received BNT162b2 messenger RNA(mRNA)coronavirus disease 2019 vaccination 3 mo before the occurrence of HSEG,and that its disappearance was confirmed 4 mo after mRNA vaccination suggested that the drug-induced sarcoidosis-like reaction(DISR)might be induced by the mRNA vaccination.Fortunately,rechallenge of drug-induced DISR with the third mRNA vaccination was not confirmed.
文摘BACKGROUND Empirical use of potentially hepatotoxic drugs in the management of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection is considered as one of the major etiopathogenetic factors for liver injury.Recent evidence has shown that an underlying genetic factor may also occur.Hence,it is important to understand the host genetics and iatrogenic-based mechanisms for liver dysfunction to make timely remedial measures.AIM To investigate drug-induced and genetic perspectives for the development of coronavirus disease 2019(COVID-19)-related liver injury.METHODS Reference Citation Analysis,PubMed,Google Scholar and China National Knowledge Infrastructure were searched by employing the relevant MeSH keywords and pertaining data of the duration,site and type of study,sample size with any subgroups and drug-induced liver injury outcome.Genetic aspects were extracted from the most current pertinent publications.RESULTS In all studies,the hepatic specific aminotransferase and other biochemical indices were more than their prescribed upper normal limit in COVID-19 patients and were found to be significantly related with the gravity of disease,hospital stay,number of COVID-19 treatment drugs and worse clinical outcomes.In addition,membrane bound O-acyltransferase domain containing 7 rs641738,rs11385942 G>GA at chromosome 3 gene cluster and rs657152 C>A at ABO blood locus was significantly associated with severity of livery injury in admitted SARS-CoV-2 patients.CONCLUSION Hepatic dysfunction in SARS-CoV-2 infection could be the result of individual drugs or due to drug-drug interactions and may be in a subset of patients with a geneticpropensity. Thus, serial estimation of hepatic indices in hospitalized SARS-CoV-2 patients shouldbe done to make timely corrective actions for iatrogenic causes to avoid clinical deterioration.Additional molecular and translational research is warranted in this regard.
文摘Drug-induced autoimmune hepatitis(DIAIH)is a specific phenotype of druginduced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation.Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline,non-steroidal anti-inflammatory drugs,statins as well as anti-tumor necrosis agents.The clinical features of druginduced liver injury are indistinguishable from idiopathic autoimmune hepatitis(AIH)as both may have positive AIH-related autoantibodies,elevated immunoglobulin G,as well as similar histopathological findings.In patients who show no clinical improvement,or there is progressive liver injury despite cessation of the suspected drug,a liver biopsy should be considered,whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH.Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury.A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper.In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature.Early identification and treatment often lead to a favorable outcome in DIAIH.
基金supported by a grant from the National Natural Science Foundation of China(81270544)
文摘Background: The diagnosis of drug-induced autoimmune hepatitis(DIAIH) and its differentiation from idiopathic autoimmune hepatitis(AIH) is challenging. This study aimed to differentiate DIAIH from AIH by comparing the biochemical changes, histological features, and frequencies of CD4~+Foxp3~+CD25+/-regulatory T cells(Tregs) in liver tissues or peripheral blood lymphocytes.Methods: A total of 15 DIAIH patients and 24 AIH patients who underwent liver biopsies at initial presentation were enrolled in this study. The liver histological changes were assessed by HE staining. The phenotypic recognition and distribution of CD4~+Foxp3~+CD25+/-Tregs in liver tissues were evaluated by single/double immunostains in serial sections. The CD4~+Foxp3~+CD25+/-Tregs in peripheral blood were analyzed by flow cytometry.Results: The median values of ALT and AST were 404.50 U/L and 454.10 U/L in DIAIH patients and309.50 U/L and 315.00 U/L in AIH patients, respectively. More importantly, for the first time we found that patients with DIAIH had higher levels of serum ALT and AST, more severe degree of lobular inflammation,higher frequencies of zone 3 necrosis and higher number of lobular CD4~+Foxp3~+CD25~-Tregs compared with AIH(P < 0.05). Furthermore, there were positive correlations in DIAIH between the degree of lobular inflammation and either the AST/ALT level or the number of lobular CD4~+Foxp3~+CD25~-Tregs(P < 0.05).However, the frequency of peripheral blood CD4~+Foxp3~+CD25+/-Tregs were not significantly different between DIAIH and AIH.Conclusions: The differences of ALT, AST and the number of lobular CD4~+Foxp3~+CD25~-Tregs between patients with DIAIH and those with AIH are clinically helpful in differentiating these two diseases in their early stage.
文摘Drug-induced liver injury(DILI)is an uncommon event in clinical practice,which makes knowing its true incidence difficult.Prospective,retrospective and registry-based studies are the most important methods to obtain epidemiological data on DILI.Latin America(LA)has a historical lack of prospective studies on this topic.New definitions and the creation of hepatotoxicity registries have significantly improved the epidemiological understanding of hepatic drug reactions in several regions of the world.The Latin American DILI network,referred to as LATINDILI,has been created in 2011,and recently published its own DILI recommendations describing the most relevant issues on the management of hepatotoxicity in general,and those based on findings from our own LA experience in particular.Although most of the registries do not carry out population-based studies,they may provide important data related to the prevalence of DILI.The joint work among researchers and the corresponding health and regulatory authorities should be stimulated due to the high impact that hepatotoxicity represents for public health.
文摘The spectrum of drug-induced liver injury （DILI） is both diverse and complex. The first step in diagnosis is a suspicion of DILl based on careful consideration of recent comprehensive reports on the disease. There are some situations in which the suspicion of DILI is particularly strong. Exclusion of other possible etiologies according to the pattern of liver injury is essential for the diagnosis. In patients with suspected DILl, diagnostic scales, such as the Councils for International Organizations of Medical Sciences/ Roussel Uclaf Causality Assessment Method （CIOMS/RUCAM） scale, may be helpful for the final diagnosis. Early management of DILl involves prompt withdrawal of the drug suspected of being responsible, according to serum levels of alanine aminotransferase （ALT）, alkaline phosphatase （ALP）, and total bilirubin （T-Bil）. However, as DILI patients may show resolution of liver injury without discontinuation of the drug, it should be carefully evaluated whether the suspected drug should be discontinued immediately with adequate consideration of the importance of the medication.
文摘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.
基金Supported by the Spanish Ministerio de Economía y Competitividad(MINECO),No.RyC 2014-15242No.SAF2016-78711 to Martinez-Naves E and Cubero FJ.Martinez-Naves E+1 种基金Cubero FJ are part of the UCM group"Lymphocyte Immunobiology",Ref.920631(imas12-associated,Ref.IBL-6)Chinese Scholarship Council fellow to YeH
文摘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.
基金by Grant-in-Aid for Scientif ic Research (Category B, No. 18390168) for K Tsukamoto by the Ministry of Education, Culture, Sports, Science and Technology of Japan
文摘AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.
文摘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
基金Supported partly by research grants from the Agencia Espaoladel Medicamento from the Fondo de Investigación Sanitaria(FIS 04-1688 and FIS 04-1759)
文摘Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.
文摘AIM: To analyze the outcome of patients with severe drug-induced liver disease (DILD) associated with jaundice classified as hepatocellular, cholestatic or mixed liver injury and to evaluate the validity of Hy’s rule and the most important predictors for outcome. METHODS: The Adverse Drug Reaction Advisory Committee was set up in 1997 in our hospital to identify all suspicions of DILD following a structured prospective report form. Liver damage was divided into hepatocellular, cholestatic, and mixed types according to laboratory and histologic criteria when available. Further evaluation of causality assessment was performed. RESULTS: From January 1997 to December 2004, 265 patients were diagnosed with DILD,and 140 (52.8%) of them were female. hepatocellular damage was the most common (72.1%), the incidence of death was 9.9% in patients with hepatocellular damage and 9.5% in patients with cholestatic/mixed damage (P < 0.05). There was no difference in age of dead and recovered patients. The proportion of females and males was similar in recovered and dead patients, no difference was observed in duration of treatment between the two groups. The serum total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and aspartate transaminase (AST) (P = 0.013) values were higher in dead patients than in recovered patients. Chinese herbal medicine was the most frequently prescribed, accounting for 24.2% of the whole series. However, antitubercular drugs (3.4%) were found to be the primary etiological factor for fetal DILD. Factors associated with the development of fulminanthepatic failure were hepatic encephalopathy (OR = 43.66, 95% CI = 8.47-224.95, P < 0.0001), ascite (OR = 28.48, 95% CI = 9.26-87.58, P < 0.0001), jaundice (OR = 11.43, 95% CI = 1.52-85.96, P = 0.003), alcohol abuse (OR = 3.83, 95% CI = 1.26-11.67, P = 0.035) and direct bilirubin (OR = 1.93, 95% CI = 1.25-2.58, P = 0.012). CONCLUSION: Death occurs in 9.8% of patients with DILD. Chinese herbal medicine stands out as the most common drug for DILD. While antitubercular drugs are found to be the primary etiological factor for fetal DILD, hepatic encephalopathy, ascites, jaundice, alcohol abuse and direct bilirubin levels are associated with the death of DILD patients.
文摘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.
基金supported by Surface Project of Shandong Provincial Natural Science Foundation(No.ZR2014HM081)
文摘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.
文摘With over 100000 hospital admissions per annum,acute pancreatitis remains the leading gastrointestinal cause of hospitalization in the United States and has farreaching impact well beyond.It has become increasingly recognized that druginduced pancreatitis(DIP),despite accounting for less than 3%of all cases,represents an important and growing though often inconspicuous cause of acute pancreatitis.Nevertheless,knowledge of DIP is often curtailed by the limited availability of evidence needed to implicate given agents,especially for nonprescription medications.Indeed,the majority of available data is derived from case reports,case series,or case control studies.Furthermore,the mechanism of injury and causality for many of these drugs remain elusive as a definitive correlation is generally not established(<10%of cases).Several classification systems have been proposed,but no single system has been widely adopted,and periodic updates are required in light of ongoing pharmacologic expansion.Moreover,infrequently prescribed medications or those available over-thecounter(including herbal and other alternative remedies)are often overlooked as a potential culprit of acute pancreatitis.Herein,we review the ever-increasing diversity of DIP and the potential mechanisms of injury with the goal of raising awareness regarding the nature and magnitude of this entity.We believe this manuscript will aid in increasing both primary and secondary prevention of DIP,thus ultimately facilitating more expedient diagnosis and a decrease in DIPrelated morbidity.
