Genetically predicted fatty liver disease and risk of psychiatric disorders: A mendelian randomization study

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)and alcohol-related liver disease(Ar-LD)constitute the primary forms of chronic liver disease,and their incidence is progressively increasing with changes in lifestyle habits.Earlier studies have do-cumented a correlation between the occurrence and development of prevalent mental disorders and fatty liver.AIM To investigate the correlation between fatty liver and mental disorders,thus ne-cessitating the implementation of a mendelian randomization(MR)study to elu-cidate this association.METHODS Data on NAFLD and ArLD were retrieved from the genome-wide association studies catalog,while information on mental disorders,including Alzheimer's disease,schizophrenia,anxiety disorder,attention deficit hyperactivity disorder(ADHD),bipolar disorder,major depressive disorder,multiple personality dis-order,obsessive-compulsive disorder(OCD),post-traumatic stress disorder(PTSD),and schizophrenia was acquired from the psychiatric genomics consor-tium.A two-sample MR method was applied to investigate mediators in signifi-cant associations.RESULTS After excluding weak instrumental variables,a causal relationship was identified between fatty liver disease and the occurrence and development of some psychia-tric disorders.Specifically,the findings indicated that ArLD was associated with a significantly elevated risk of developing ADHD(OR:5.81,95%CI:5.59-6.03,P<0.01),bipolar disorder(OR:5.73,95%CI:5.42-6.05,P=0.03),OCD(OR:6.42,95%CI:5.60-7.36,P<0.01),and PTSD(OR:5.66,95%CI:5.33-6.01,P<0.01).Meanwhile,NAFLD significantly increased the risk of developing bipolar disorder(OR:55.08,95%CI:3.59-845.51,P<0.01),OCD(OR:61.50,95%CI:6.69-565.45,P<0.01),and PTSD(OR:52.09,95%CI:4.24-639.32,P<0.01).CONCLUSION Associations were found between genetic predisposition to fatty liver disease and an increased risk of a broad range of psychiatric disorders,namely bipolar disorder,OCD,and PTSD,highlighting the significance of preven-tive measures against psychiatric disorders in patients with fatty liver disease.

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.

Non-alcoholic fatty liver disease and sleep disorders

Studies have shown that non-alcoholic fatty liver disease(NAFLD)may be associated with sleep disorders.In order to explore the explicit relationship between the two,we systematically reviewed the effects of sleep disorders,especially obstructive sleep apnea(OSA),on the incidence of NAFLD,and analyzed the possible mechanisms after adjusting for confounding factors.NAFLD is independently associated with sleep disorders.Different sleep disorders may be the cause of the onset and aggravation of NAFLD.An excessive or insufficient sleep duration,poor sleep quality,insomnia,sleep-wake disorders,and OSA may increase the incidence of NAFLD.Despite that some research suggests a unidirectional causal link between the two,specifically,the onset of NAFLD is identified as a result of changes in sleep characteristics,and the reverse relationship does not hold true.Nevertheless,there is still a lack of specific research elucidating the reasons behind the higher risk of developing sleep disorders in individuals with NAFLD.Further research is needed to establish a clear relationship between NAFLD and sleep disorders.This will lay the groundwork for earlier identification of potential patients,which is crucial for earlier monitoring,diagnosis,effective prevention,and treatment of NAFLD.

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.

Therapeutic interventions of acute and chronic liver disorders:A comprehensive review

Liver disorders are one of the most common pathological problems worldwide.It affects more than 1.5 billion worldwide.Many types of hepatic cells have been reported to be involved in the initiation and propagation of both acute and chronic liver diseases,including hepatocytes,Kupffer cells,sinusoidal endothelial cells,and hepatic stellate cells(HSCs).In addition,oxidative stress,cytokines,fibrogenic factors,microRNAs,and autophagy are also involved.Understanding the molecular mechanisms of liver diseases leads to discovering new therapeutic interventions that can be used in clinics.Recently,antioxidant,anti-inflammatory,anti-HSCs therapy,gene therapy,cell therapy,gut microbiota,and nanoparticles have great potential for preventing and treating liver diseases.Here,we explored the recent possible molecular mechanisms involved in the pathogenesis of acute and chronic liver diseases.Besides,we overviewed the recent therapeutic interventions that targeted liver diseases and summarized the recent studies concerning liver disorders therapy.

Huangqin decoction alleviates lipid metabolism disorders and insulin resistance in nonalcoholic fatty liver disease by triggering Sirt1/NF-κB pathway

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is a clinicopathological entity characterized by intrahepatic ectopic steatosis.As a consequence of increased consumption of high-calorie diet and adoption of a sedentary lifestyle,the incidence of NAFLD has surpassed that of viral hepatitis,making it the most common cause of chronic liver disease globally.Huangqin decoction(HQD),a Chinese medicinal formulation that has been used clinically for thousands of years,has beneficial outcomes in patients with liver diseases,including NAFLD.However,the role and mechanism of action of HQD in lipid metabolism disorders and insulin resistance in NAFLD remain poorly understood.AIM To evaluate the ameliorative effects of HQD in NAFLD,with a focus on lipid metabolism and insulin resistance,and to elucidate the underlying mechanism of action.METHODS High-fat diet-induced NAFLD rats and palmitic acid(PA)-stimulated HepG2 cells were used to investigate the effects of HQD and identify its potential mechanism of action.Phytochemicals in HQD were analyzed by highperformance liquid chromatography(HPLC)to identify the key components.RESULTS Ten primary chemical components of HQD were identified by HPLC analysis.In vivo,HQD effectively prevented rats from gaining body and liver weight,improved the liver index,ameliorated hepatic histological aberrations,decreased transaminase and lipid profile disorders,and reduced the levels of pro-inflammatory factors and insulin resistance.In vitro studies revealed that HQD effectively alleviated PA-induced lipid accumulation,inflammation,and insulin resistance in HepG2 cells.In-depth investigation revealed that HQD triggers Sirt1/NF-κB pathwaymodulated lipogenesis and inflammation,contributing to its beneficial actions,which was further corroborated by the addition of the Sirt1 antagonist EX-527 that compromised the favorable effects of HQD.CONCLUSION In summary,our study confirmed that HQD mitigates lipid metabolism disorders and insulin resistance in NAFLD by triggering the Sirt1/NF-κB pathway.

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.

Clinical Observation on Modified Huan'gan Lipi Decoction Combined with Acupuncture in Treating Spleen Deficiency and Liver Hyperactivity Type Tic Disorders

[Objectives]To observe the clinical efficacy of Modified Huan'gan Lipi Decoction combined with acupuncture in the treatment of spleen deficiency and liver hyperactivity type tic disorders(TD).[Methods]Sixty patients with spleen deficiency and liver hyperactivity type TD were randomly divided into a treatment group of 40 cases and a control group of 20 cases.The treatment group received Modified Huan'gan Lipi Decoction combined with acupuncture,and the control group received Haloperidol Tablets.After 4 weeks of treatment,the Yale Global Tic Severity Scale(YGTSS)score,the total score of TCM syndrome and the clinical efficacy were compared between the two groups before and after treatment.[Results]After treatment,the total effective rate of 87.5%in the treatment group was higher than 80.0%in the control group(P>0.05);the total score of YGTSS and the total score of TCM syndromes in the two groups were compared within groups,P﹤0.01;between groups,P﹤0.01.The recurrence rates of the treatment group and the control group were 11.1%and 71.4%,respectively.The difference between the two groups was statistically significant(P﹤0.01).[Conclusions]Modified Huan'gan Lipi Decoction combined with acupuncture in the treatment of spleen deficiency and liver hyperactivity type TD can significantly improve the patient's tic symptoms,and its long-term efficacy is stable.

Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease

MicroRNAs(miRNAs) are small non-coding RNAs that regulate multiple physiological and pathological functions through the modulation of gene expression at the post-transcriptional level. Accumulating evidence has established a role for miRNAs in the development and pathogenesis of liver disease. Specifically, a large number of studies have assessed the role of miRNAsin alcoholic liver disease(ALD) and non-alcoholic fatty liver disease(NAFLD), two diseases that share common underlying mechanisms and pathological characteristics. The purpose of the current review is to summarize and update the body of literature investigating the role of miRNAs in liver disease. In addition, the potential use of miRNAs as biomarkers and/or therapeutic targets is discussed. Among all miRNAs analyzed, miR-34 a, miR-122 and miR-155 are most involved in the pathogenesis of NAFLD. Of note, these three miRNAs have also been implicated in ALD, reinforcing a common disease mechanism between these two entities and the pleiotropic effects of specific miRNAs. Currently, no single miRNA or panel of miRNAs has been identified for the detection of, or staging of ALD or NAFLD. While promising results have been shown in murine models, no therapeutic based-miRNA agents have been developed for use in humans with liver disease.

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.

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

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

From chronic liver disorders to hepatocellular carcinoma: Molecular and genetic pathways

Hepatocarcinogenesis is a process attributed to progressive genomic changes that alter the hepatocellular phenotype producing cellular intermediates that evolve into hepatocellular carcinoma (HCC). During the preneoplastic phase, the liver is often the site of chronic hepatitis and/or cirrhosis, and these conditions induce liver regeneration with accelerated hepatocyte cycling in an organ that is otherwise proliferatively at rest. Hepatocyte regeneration is accelerated by upregulation of mitogenic pathways involving molecular and genetic mechanisms. Hepatic growth factors, inhibitors and triggers may also play a role. This process leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomerase reexpression, microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and the emergence of HCC are associated with the accumulation of irreversible structural alterations in genes and chromosomes even if the genomic basis of the malignant phenotype is largely heterogeneous. Therefore, a malignant hepatocyte phenotype may be produced by changes in genes acting through different regulatory pathways, thus producing several molecular variants of HCC. On these bases, a key point for future research will be to determine whether the deletions are specific, due to particular loci in the minimally deleted regions of affected chromosome arms, or whether they are nonspecific with loss of large portions of chromosomes or entire chromosome arms leading to passive deletion of loci. The final aim is the possibility of identifying a step where carcinogenetic processes could be terminated.

CD4+Foxp3+CD25+/-Tregs characterize liver tissue specimens of patients suffering from drug-induced autoimmune hepatitis:A clinical-pathological study

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.

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

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

Urea cycle disorders:A case report of a successful treatment with liver transplant and a literature review

The urea cycle is the final pathway for nitrogen metabolism. Urea cycle disorders(UCDs) include a variety of genetic defects, which lead to inefficient urea synthesis. Elevated blood ammonium level is usually dominant in the clinical pattern and the primary manifestations affect the central nervous system. Herein, we report the case of a 17-year-old girl who was diagnosed with UCD at the age of 3. Despite a controlled diet, she was hospitalized several times for acute attacks with recurrent life risk. She came to our attention for a hyperammonemic episode. We proposed an orthotopic liver transplant(OLT) as a treatment; the patient and her family were in complete agreement. On February 28, 2007, she successfully received a transplant. Following the surgery, she has remained well, and she is currently leading a normal life. Usually for UCDs diet plays the primary therapeutic role, while OLT is often considered as a last resort. Our case report and the recent literature data on the quality of life and prognosis of traditionally treated patients vs OLT patients, support OLT as a primary intervention to prevent life-threatening acute episodes and chronic mental impairment.

Drug-induced liver injury and COVID-19:A review for clinical practice

Coronavirus disease 2019(COVID-19)consists of a systemic disease that can present many complications.The infection presents broad clinical symptoms and a high rate of transmissibility.In addition to severe acute respiratory syndrome,the patients manifest complications beyond the respiratory system.The frequency of liver damage in COVID-19 patients ranges from 14.8% to 53% of patients.One should pay attention to drug-induced liver injury(DILI)in patients with COVID-19,especially considering the off-label use of drugs in prophylactic and therapeutic regimens applied on large scales.This review aims to present relevant information on the medication used so far in COVID-19 patients and its possible hepatotoxicity.We reviewed liver damage in patients with COVID-19 on PubMed and Virtual Health Library to investigate DILI cases.Four studies were selected,involving the medicines remdesivir,tocilizumab and a pharmacovigilance analysis study.The hepatotoxicity profile of drugs presented in the literature considers use in accordance to usual posology standards for treatment.However,drugs currently used in the management of COVID-19 follow different dosages and posology than those tested by the pharmaceutical industry.The deficiency of uniformity and standardization in the assessment of hepatotoxicity cases hinders the publication of information and the possibility of comparing information among healthcare professionals.It is suggested that severe liver injury in COVID-19 patients should be reported in pharmacovigilance institutions,and physicians should pay attention to any considerable abnormal liver test elevation as it can demonstrate unknown drug hepatotoxicity.Liver disorders in COVID-19 patients and the use of several concomitant off-label medications—with a potential risk of further damaging the liver-should at least be a warning sign for rapid identification and early intervention,thus preventing liver damage from contributing to severe impairment in patients.

Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report

The United States Food and Drug Administration recently warned that the direct acting antiviral(DAA) combination hepatitis C virus(HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin(PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis(compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment withPODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R.