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.

Effects of Yigan Capsule on the expression of HMGB1,RAGE and NF-κB protein in rats with drug-induced liver injury

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.

Expert Consensus on the Diagnosis and Treatment of Anticancer Drug-Induced Interstitial Lung Disease

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.

Contribution of gut microbiota to drug-induced liver injury

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.

Drug-induced entero-colitis due to interleukin-17 inhibitor use;capsule endoscopic findings and pathological characteristics:A case report

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.

COVID-19-related liver injury:Focus on genetic and drug-induced perspectives

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.

Drug-induced sarcoidosis-like reaction three months after BNT162b2 mRNA COVID-19 vaccination:A case report and review of literature

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.

A rapid and visual detection method for Crimean-Congo hemorrhagic fever virus by targeting S gene

Crimean-Congo hemorrhagic fever(CCHF)is a zoonotic disease caused by the CCHF virus(CCHFV),which is primarily transmitted by ticks(Lorenzo Juanes et al.2023).It is an emerging disease that occurs sporadically in Africa,Asia,and Europe,with a high morbidity and mortality rate,as high as 30%in humans(Ceylan et al.2013).CCHFV,belonging to genus Nairovirus,family Bunyaviridae,was first identified in the Congo in the 1960s.

The global,prevalence,and risk factors of postoperative fever after percutaneous nephrolithotomy:A systematic review and meta-analysis

Objective:This study aimed to explore the global,prevalence,and risk factors of fever after percutaneous nephrolithotomy(PCNL)by conducting a systematic review and meta-analysis.Methods:The high-sensitivity searching was conducted without time limitation until December 30,2020 in Web of Sciences,Scopus,and PubMed based on inclusion and exclusion criteria.Results:The prevalence rates of fever and sepsis among patient undergoing PCNL were estimated 9.5%(95%confidence interval[CI]:9.3%-9.7%),and 4.5%(95%CI:4.2%-4.8%),respectively.Nephrostomy tube was used in 9.96%(95%CI:9.94%-9.97%)of patients.The mean preoperative white blood cells of patients were 6.401×109/L;18.3%and 4.55%of patients were considered as the positive urinary culture and pyuria,respectively.About 20.4%of patients suffered from residual stones.The odds ratios(ORs)of fever in patients who suffering from diabetes mellitus,hydronephrosis,staghorn stones,and blood transfusion were 4.62(95%CI:2.95-7.26),1.04(95%CI:0.81-1.34),2.57(95%CI:0.93-7.11),and 2.65(95%CI:1.62-4.35),respectively.Patients who underwent PCNL in prone position were more likely to develop fever(OR:1.23;95%CI:0.75-2.00)than patients in supine position.Conclusion:The current study showed that patients who suffer from diabetes mellitus,hydronephrosis,staghorn stones,nephrostomy tube or double-J stent,blood transfusion,and also patients who underwent PCNL in prone position surgery are more likely to develop a postoperative fever after PCNL.

Global systematic review and meta-analysis of knowledge, attitudes, and practices towards dengue fever among the general population

Objective:To determine the global level of knowledge,attitudes,and practices towards dengue fever among the general population.Methods:To complete this systematic review and meta-analysis,a thorough search for pertinent English-language literature was undertaken during the study's extension until October 2023.The search used Google Scholar,Scopus,PubMed/MEDLINE,Science Direct,Web of Science,EMBASE,Springer,and ProQuest.A quality assessment checklist developed using a modified Newcastle-Ottawa Scale for the cross-sectional study was used to evaluate the risk of bias in the included papers.Inverse variance and Cochran Q statistics were employed in the STATA software version 14 to assess study heterogeneity.When there was heterogeneity,the Dersimonian and Liard random-effects models were used.Results:59 Studies totaling 87353 participants were included in this meta-analysis.These investigations included 86278 participants in 55 studies on knowledge,20196 in 33 studies on attitudes,and 74881 in 29 studies on practices.The pooled estimates for sufficient knowledge,positive attitudes,and dengue fever preventive behaviors among the general population were determined as 40.1%(95%CI 33.8%-46.5%),46.8%(95%CI 35.8%-58.9%),and 38.3%(95%CI 28.4%-48.2%),respectively.Europe exhibits the highest knowledge level at 63.5%,and Africa shows the lowest at 20.3%.Positive attitudes are most prevalent in the Eastern Mediterranean(54.1%)and Southeast Asia(53.6%),contrasting sharply with the Americas,where attitudes are notably lower at 9.05%.Regarding preventive behaviors,the Americas demonstrate a prevalence of 12.1%,Southeast Asia at 28.1%,Western Pacific at 49.6%,Eastern Mediterranean at 44.8%,and Africa at 47.4%.Conclusions:Regional disparities about the knowledge,attitude and preventive bahaviors are evident with Europe exhibiting the highest knowledge level while Africa has the lowest.These findings emphasize the importance of targeted public health interventions tailored to regional contexts,highlighting the need for region-specific strategies to enhance dengue-related knowledge and encourage positive attitudes and preventive behaviors.

Protectivity of Freeze Dried Inactivated Rift Valley Fever Vaccine

Background: Vaccinations for animals are crucial for food production, animal welfare, public health, and animal health. They are an affordable way to stop animal sickness, increase food production efficiency, and lessen or stop the spread of zoonotic diseases to humans. Animal vaccines that are both safe and efficacious are vital to modern culture. The vaccine should induce a strong, protective and prolonged immune response against the antigenic factor. In order to achieve these goals, novel vaccination techniques and an efficient adjuvant are required to render the vaccine immunogenically protective and trigger a strong immune response. Aim: Our study aims to promote and enhance the immunogenicity against RVF virus disease through lyophilized inactivated RVF vaccine through induction of early cellular, high and prolonged humeral immunity in vaccinated animals using cabopol as stabilizer and Saponin or normal saline as a diluent at time of vaccination. Moreover, manufacturing of these vaccines is easy to be done. Results: The gained results revealed that RVF freeze-dried vaccine with Carbopol that reconstituted using Saponin elicited better immune response than that reconstituted using normal saline (NaCl). The cell mediated immune response as represented by lymphocyte blastogenesis and phagocytic activity were markedly increased with high levels when we used Saponin as a diluent than that in group vaccinated with vaccine diluted with NaCl, on the other side the humeral immune response in group vaccinated using the Saponin as diluent is more detected and stayed within the protective level till the end of 11th month post vaccination (1.5 TCID50) while the immune response induced after using normal saline as a diluent stayed within the protective level till the end of 10th month post vaccination (1.8 TCID50). Conclusion: The use of Saponin as a diluent for reconstitution of the freeze dried RVF vaccine is preferable than the use of normal saline enhancing both sheep cellular and humeral immune response.

Establishment of an indirect immunofluorescence assay for the detection of African swine fever virus antibodies

African swine fever(ASF)continues to cause enormous economic loss to the global pig industry.Since there is no safe and effective vaccine,accurate and timely diagnosis of ASF is essential to implement control measures.Indirect immunofluorescence assay(IFA)is a gold standard serological method recommended by the World Organization for Animal Health(WOAH).In this study,we used primary fetal kidney cells to establish a wild boar cell line(BK2258)that supported the efficient replication of ASF virus(ASFV)SD/DY-I/21 and showed visible cytopathic effect(CPE).Moreover,using BK2258,we established a sensitive and specific IFA for ASFV antibody detection.To standardize and evaluate the performance of this assay,we used serum samples from pigs infected with the low virulent genotype I SD/DY-I/21 and genotype II HLJ/HRB1/20,and immunized with the vaccine candidate HLJ/18-7GD,field samples,and negative serum samples.The IFA reacted with the ASFV-positive sera and displayed bright fluorescence foci.There was no non-specific green fluorescence due to cellular senescence or other cell damage-causing factors.Compared to a commercial indirect enzyme-linked immunosorbent assay(iELISA),ASFV antibodies were detected 1–4 days earlier using our IFA.The detection limits of the IFA and iELISA for the same ASFV-antibody positive serum samples were 1:25,600 and 1:6,400,respectively,indicating that the IFA is more sensitive than iELISA.The newly established IFA was highly specific and did not cross-react with sera positive for six other important porcine pathogens(i.e.,Classical swine fever virus(CSFV),Porcine reproductive and respiratory syndrome virus(PRRSV),Porcme circovirus type 2(PCV2),Pseudorabies virus(PRV),Foot-and-Mouth disease virus type O(FMDV/O),and Porcine epidemic diarrhea virus(PEDV)).This study thus provides a sensitive,specific,and reliable detection method that is suitable for the serological diagnosis of ASF.

Geographically and Temporally Weighted Regression in Assessing Dengue Fever Spread Factors in Yunnan Border Regions

Objective This study employs the Geographically and Temporally Weighted Regression(GTWR)model to assess the impact of meteorological elements and imported cases on dengue fever outbreaks,emphasizing the spatial-temporal variability of these factors in border regions.Methods We conducted a descriptive analysis of dengue fever’s temporal-spatial distribution in Yunnan border areas.Utilizing annual data from 2013 to 2019,with each county in the Yunnan border serving as a spatial unit,we constructed a GTWR model to investigate the determinants of dengue fever and their spatio-temporal heterogeneity in this region.Results The GTWR model,proving more effective than Ordinary Least Squares(OLS)analysis,identified significant spatial and temporal heterogeneity in factors influencing dengue fever’s spread along the Yunnan border.Notably,the GTWR model revealed a substantial variation in the relationship between indigenous dengue fever incidence,meteorological variables,and imported cases across different counties.Conclusion In the Yunnan border areas,local dengue incidence is affected by temperature,humidity,precipitation,wind speed,and imported cases,with these factors’influence exhibiting notable spatial and temporal variation.

Dengue hemorrhagic fever with rectus sheath hematoma:A case report

Rationale:Acute pain is a medical emergency that requires prompt abdominal evaluation and management.Dengue,a mosquito-borne arboviral infection,can lead to complications such as acute abdominal pain.Patient concerns:A 72-year-old hypertensive female presented with high-grade intermittent fever with chills and rigors for four days.She was diagnosed with dengue fever(NS1Ag-reactive)the day before admission.A contrast-enhanced computed tomography of the abdomen showed a hematoma along the rectus sheath which was managed conservatively as per surgical opinion.Diagnosis:Dengue hemorrhagic fever with rectus sheath hematoma.Interventions:Blood transfusion and fluid therapy.Outcomes:Ten days after discharge,the patient reproted no pain in the right iliac fossa and the size of the hematoma was significantly reduced.Lessons:Although it is rarely seen as a cause of acute abdomen,complaints of adnominal pain should never be ignored in critical or convalescent phase of dengue fever.Radiological investigations should be promptly conducted as hematoma is often difficult to be diagnosed clinically.Delay in diagnosis of rectus sheath hematoma can be fatal.

Effect of Milk Processed Arnebiae Radix on Body Temperature of Fever Rats

[Objectives]To investigate the synergistic effect of Arnebiae Radix after processing.[Methods]The effects of raw Arnebiae Radix and milk processed Arnebiae Radix on hypothermia in yeast-induced febrile rats were compared.[Results]The processed and unprocessed Arnebiae Radix at high,medium and low doses all had a certain effect on inhibiting the rise of body temperature in rats.The high dose unprocessed group,the medium dose processed group and the high dose processed group had the best inhibitory effect on body temperature,the low dose processed group could delay the fever time,and the low dose unprocessed group had poor inhibitory effect on fever.[Conclusions]The prepared Arnebiae Radix has enhanced drug effect,and milk processed Arnebiae Radix can be used to replace common Arnebiae Radix to reduce the dosage of Arnebiae Radix and save Arnebiae Radix resources.

Fever assessment in children under five: Are we following the guidelines?

BACKGROUND Fever is a common cause of medical consultation and hospital admission,particularly among children.Recently,the United Kingdom’s National Institute for Health and Care Excellence(NICE)updated its guidelines for assessing fever in children under five years of age.The efficient assessment and management of children with fever are crucial for improving patient outcomes.AIM To evaluate fever assessment in hospitalized children and to assess its adherence with the NICE Fever in under 5s guideline.METHODS We conducted a retrospective cohort review of the electronic medical records of children under five years of age at the Department of Pediatrics,Salmaniya Medical Complex,Bahrain,between June and July 2023.Demographic data,vital signs during the first 48 h of admission,route of temperature measurement,and indications for admission were gathered.Fever was defined according to the NICE guideline.The children were divided into five groups according to their age(0-3 months,>3-6 months,>6-12 months,>12-36 months,and>36-60 months).Patients with and without fever were compared in terms of demography,indication for admission,route of temperature measurement,and other vital signs.Compliance with the NICE Fever in the under 5s guideline was assessed.Full compliance was defined as>95%,partial compliance as 70%-95%,and minimal compliance as≤69%.Pearson’sχ^(2),Student’s t test,the Mann-Whitney U test,and Spearman’s correlation coefficient(rs)were used for comparison.RESULTS Of the 136 patients reviewed,80(58.8%)were boys.The median age at admission was 14.2[interquartile range(IQR):1.7-44.4]months,with the most common age group being 36-60 months.Thirty-six(26.4%)patients had fever,and 100(73.6%)were afebrile.The commonest age group for febrile patients(>12-36 months)was older than the commonest age group for afebrile patients(0-3 months)(P=0.027).The median weight was 8.3(IQR:4.0-13.3)kg.Patients with fever had higher weight than those without fever[10.2(IQR:7.3-13.0)vs 7.1(IQR:3.8-13.3)kg,respectively](P=0.034).Gastrointestinal disease was the leading indication for hospital admission(n=47,34.6%).Patients with central nervous system diseases and fever of unknown etiology were more likely to be febrile(P=0.030 and P=0.011,respectively).The mean heart rate was higher in the febrile group than the afebrile group(140±24 vs 126±20 beats per minute,respectively)[P=0.001(confidence interval:5.8-21.9)]with a positive correlation between body temperature and heart rate,r=0.242,n=136,P=0.004.A higher proportion of febrile patients received paracetamol(n=35,81.3%)compared to the afebrile patients(n=8,18.6%)(P<0.001).The axillary route was the most commonly used for temperature measurements(n=40/42,95.2%),followed by the rectal route(n=2/42,4.8%).The department demonstrated full compliance with the NICE guideline for five criteria:the type of thermometer used,route and frequency of temperature measurement,frequency of heart rate measurement,and use of antipyretics as needed.Partial compliance was noted for two criteria,the threshold of fever at 38°C or more,and the respiratory rate assessment in febrile patients.Minimal compliance or no record was observed for the remaining three criteria;routine assessment of capillary refill,temperature reassessment 1-2 h after each antipyretic intake,and refraining from the use of tepid sponging.CONCLUSION This study showed that fever assessment in hospitalized children under five years of age was appropriate,but certain areas of adherence to the NICE guideline still need to be improved.

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

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.

Contemporary review of drug-induced pancreatitis: A different perspective

Although gallstone and alcohol use have been consid-ered the most common causes of acute pancreatitis, hundreds of frequently prescribed medications are as-sociated with this disease state. The true incidence is unknown since there are few population based studies available. The knowledge of drug induced acute pan-creatitis is limited by the availability and the quality of the evidence as the majority of data is extrapolated from case reports. Establishing a definitive causal rela-tionship between a drug and acute pancreatitis poses a challenge to clinicians. Several causative agent classifi-cation systems are often used to identify the suspected agents. They require regular updates since new drug induced acute pancreatitis cases are reported continu-ously. In addition, infrequently prescribed medications and herbal medications are often omitted. Furthermore, identification of drug induced acute pancreatitis with new medications often requires accumulation of post market case reports. The unrealistic expectation for a comprehensive list of medications and the multifacto-rial nature of acute pancreatitis call for a different ap-proach. In this article, we review the potential mecha-nisms of drug induced acute pancreatitis and providethe perspective of deductive reasoning in order to allow clinicians to identify potential drug induced acute pan-creatitis with limited data.