Reabsorption of iron into acutely damaged rat liver:A role for ferritins

AIM To studied iron metabolism in liver, spleen, and serum after acute liver-damage, in relation to surrogate markers for liver-damage and repair.METHODS Rats received intraperitoneal injection of the hepatotoxin thioacetamide(TAA), and were sacrificed regularly between 1 and 96 h thereafter. Serum levels of transaminases and iron were measured using conventional laboratory assays. Liver tissue was used for conventional histology, immunohistology, and iron staining. The expression of acute-phase cytokines, ferritin light chain(FTL), and ferritin heavy chain(FTH)was investigated in the liver by q RT-PCR. Western blotting was used to investigate FTL and FTH in liver tissue and serum. Liver and spleen tissue was also used to determine iron concentrations.RESULTS After a short initial decrease, iron serum concentrations increased in parallel with serum transaminase(aspartate aminotransferase and alanine aminotransferase) levels, which reached a maximum at 48 h, and decreased thereafter. Similarly, after 48 h a significant increase in FTL, and after 72 h in FTH was detected in serum. While earliest morphological signs of inflammation in liver were visible after 6 h, increased expression of the two acute-phase cytokines IFN-γ(1 h) and IL-1β(3 h) was detectable earlier, with maximum values after 12-24 h. Iron concentrations in liver tissue increased steadily between 1 h and 48 h, and remained high at 96 h. In contrast, spleen iron concentrations remained unchanged until 48 h, and increased mildly thereafter(96 h). Although tissue iron staining was negative, hepatic FTL and FTH protein levels were strongly elevated. Our results reveal effects on hepatic iron concentrations after direct liver injury by TAA. The increase of liver iron concentrations may be due to the uptake of a significant proportion of the metal by healthy hepatocytes, and only to a minor extent by macrophages, as spleen iron concentrations do not increase in parallel. The temporary increase of iron, FTH and transaminases in serum is obviously due to their release by damaged hepatocytes.CONCLUSION Increased liver iron levels may be the consequence of hepatocyte damage. Iron released into serum by damaged hepatocytes is obviously transported back and stored via ferritins.

Acute liver failure caused by drug-induced hypersensitivity syndrome associated with hyperferritinemia

Drug-induced hypersensitivity syndrome(DIHS) is a severe reaction usually characterized by fever,rash,and multiorgan failure,occurring 2-6 wk after drug introduction.It is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release.A 54-year-old woman was diagnosed with rheumatic arthritis and initiated salazosulfapyridine by mouth.About 10 d later,she had a high fever,skin rash and liver dysfunction.She was admitted to hospital and diagnosed with a drug eruption.She was treated with oral prednisolone 30 mg/d;however,she developed high fever again and her blood tests showed acute liver failure and cytopenia associated with hyperferritinemia.She was diagnosed with acute liver failure and hemophagocytosis caused by DIHS.She was transferred to the Department of Medicine and Bioregulatory Science,Kyushu University,where she was treated with arterial steroid injection therapy.Following this treatment,her liver function improved and serum ferritin immediately decreased.We hypothesized that an immune-mediated reaction in DIHS may have generated over-activation of macrophages and T-lymphocytes,followed by a cytokine storm that affected various organs.The measurement of serum ferritin might be a useful marker of the severity of DIHS.

Effects of Phentolamine on Hemorrheology and Hemodynamics in Dogs with Acute Liver Damage

The effects of phentolamine on hemorrheology and hemodynamics were studied in dogs with acute liver damage induced by acetaminophen. After 1 h of phentolamine application , the viscosity of plasma and whole blood was significantly diminished. The hematocrit readings followed the same pattern as the alterations in viscosity. The portal venous resistance and the value of K were remarkably decreased and the portal venous blood flow was obviously increased. It can be assumed , therefore , that the decrease in viscosity induced by phentolamine results from internal hemodilution and phentolamine may improve hepatic blood circulation through the decrease of portal venous resistance caused by the reduction of blood viscosity and the dilation of portal vascular beds.

An Experimental Study on the Disturbance of Liver Circulation and the Change of Hemorrheology in Dogs with Acute Liver Damage

The changes of hepatic hemodynamics and hemorrheology were investigated in dogs with acute liver damage inducted by acetaminophen There were remarkable disturtance in liver circulation and hemorrheological abnormality occuring in both slight and severe liver damage.The study indicated that the degree of disturbance in liver circulation as well as in lemorheological change is positively correlated with the severity of livei damage For example,marked increase in blood viscosity linked with elevated fibrinogen level appeared in slight liver damage,whereas reduced blood viscosity associated with decreased plasma fibrinogen level and hematocrit occured in severe liver damage.This study also revealed that the inciease of portal venous resistance(PVR)and the disturbance of liver circulation in slight liver damage were chiefly related to the increase of blood viscosity and the increase of PVR in severe liver damage was mainly associated with the reduction of the radius of porta vein.

Risk factors related to significant hepatic inflammation in patients with acute drug-induced liver injury

Background and aims:Currently,research on biopsy-proven acute drug-induced liver injury(DILI)remains limited.This study aimed to identify clinical characteristics and risk factors for significant hepatic inflammation in patients with acute DILI.Methods:An ambispective cohort study was conducted on biopsy-proven acute DILI patients admitted to our hospital from 2012 to 2018.Using the Scheuer scoring system,patients were categorized into G0-2 or G3-4 groups and followed up for 12 months after first admission.Clinical characteristics and outcomes were retrieved from medical records.Results:The median age of the 157 enrolled patients(65.6%female)was 40.4(interquartile range(IQR),31.9-49.1)years.The median latency and length of hospitalization were 30.0(IQR,5.0-60.0)and 18.0(IQR,12.0-26.0)days.The proportions of patients in the G0-2 and G3-4 groups were 54.8%and 45.2%,respectively.Logistic regression analysis revealed that females(odds ratio(OR):2.623,95%confidence interval(CI):1.169-5.887,p=0.019),higher body mass index(OR:1.168,95%CI:1.029-1.325,p=0.016),higher total bilirubin(OR:1.004,95%CI:1.000-1.007,p=0.047),and lower prothrombin activity(OR:0.976,95%CI:0,957-0.995,p=0.013)were associated with significant hepatic inflammation.The predominance of the hepatocellular injury pattern(60.5%)at admission transformed into a predominance of the cholestatic pattern(60.5%)at discharge.During follow-up,23 patients(14.6%)developed chronic DILI,with nine patients(5.7%)progressing to cirrhosis.Moreover,15 female patients(9.6%)developed autoimmunity(3cases in the G0-2 group vs 12 cases in the G3-4 group,p<0.05).Conclusion:Acute DILI patients with high-risk factors were more likely to develop significant hepatic inflammation,and females with significant inflammation were at a higher risk of developing autoimmunity during follow-up.

Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis-a single center experience of 52 adult patients

AIM To investigate potential triggering factors leading to acute liver failure(ALF) as the initial presentation of autoimmune hepatitis(AIH).METHODS A total of 565 patients treated at our Department between 2005 and 2017 for histologically-proven AIH were retrospectively analyzed. However, 52 patients(9.2%) fulfilled the criteria for ALF defined by the "American Association for the Study of the Liver(AASLD)". According to this definition, patients with "acute-on-chronic" or "acute-on-cirrhosis" liver failure were excluded. Following parameters with focus on potential triggering factors were evaluated: Patients' demographics, causation of liver failure, laboratory data(liver enzymes, MELD-score, autoimmune markers, virus serology), liver histology, immunosuppressive regime, and finally, outcome of our patients.RESULTS The majority of patients with ALF were female(84.6%) and mean age was 43.6 ± 14.9 years. Interestingly, none of the patients with ALF was positive for antiliver kidney microsomal antibody(LKM). We could identify potential triggering factors in 26/52(50.0%) of previously healthy patients presenting ALF as their first manifestation of AIH. These were drug-induced ALF(57.7%), virus-induced ALF(30.8%), and preceding surgery in general anesthesia(11.5%), respectively. Unfortunately, 6 out of 52 patients(11.5%) did not survive ALF and 3 patients(5.7%) underwent liver transplantation(LT). Comparing data of survivors and patients with non-recovery following treatment, MELDscore(P < 0.001), age(P < 0.05), creatinine(P < 0.01), and finally, ALT-values(P < 0.05) reached statistical significance. CONCLUSION Drugs, viral infections, and previous surgery may trigger ALF as the initial presentation of AIH. Advanced age and high MELD-score were associated with lethal outcome.

Drug-induced liver injury: Do we know everything?

Interest in drug-induced liver injury(DILI) has dramatically increased over the past decade, and it has become a hot topic for clinicians, academics, pharmaceutical companies and regulatory bodies. By investigating the current state of the art, the latest scientific findings, controversies, and guidelines, this review will attempt to answer the question: Do we know everything? Since the first descriptions of hepatotoxicity over 70 years ago, more than 1000 drugs have been identified to date, however, much of our knowledge of diagnostic and pathophysiologic principles remains unchanged. Clinically ranging from asymptomatic transaminitis and acute or chronic hepatitis, to acute liver failure, DILI remains a leading causes of emergent liver transplant. The consumption of unregulated herbal and dietary supplements has introduced new challenges in epidemiological assessment and clinician management. As such, numerous registries have been created, including the United States Drug-Induced Liver Injury Network, to further our understanding of all aspects of DILI. The launch of Liver Tox and other online hepatotoxicity resources has increased our awareness of DILI. In 2013, the first guidelines for the diagnosis and management of DILI, were offered by the Practice Parameters Committee of the American College of Gastroenterology, and along with the identification of risk factors and predictors of injury, novel mechanisms of injury, refined causality assessment tools, and targeted treatment options have come to define the current state of the art, however, gaps in our knowledge still undoubtedly remain.

Mesenchymal stromal cell-dependent immunoregulation in chemically-induced acute liver failure

Drug-induced liver injury(DILI),which refers to liver damage caused by a drug or its metabolites,has emerged as an important cause of acute liver failure(ALF)in recent years.Chemically-induced ALF in animal models mimics the pathology of DILI in humans;thus,these models are used to study the mechanism of potentially effective treatment strategies.Mesenchymal stromal cells(MSCs)possess immunomodulatory properties,and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF.Here,we summarize some of the existing research on the interaction between MSCs and immune cells,and discuss the possible mechanisms underlying the immunomodulatory activity of MSCs in chemically-induced ALF.We conclude that MSCs can impact the phenotype and function of macrophages,as well as the differentiation and maturation of dendritic cells,and inhibit the proliferation and activation of T lymphocytes or B lymphocytes.MSCs also have immunomodulatory effects on the production of cytokines,such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6,in animal models.Thus,MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.

Protective Effect of Chlorogenic Acid against Carbon Tetrachloride-induced Acute Liver Damage in Rats

Objective To evaluate the protective effect of chlorogenic acid （CGA） on carbon tetrachloride （CCh）-induced liver injury of rats. Methods The anti-oxidative activity of CGA was investigated with several established in vitro systems. The hepatoprotective activity of CGA against CCI4-induced acute liver injury in eats was studied. The levels of alanine aminotranferase （ALT）, aspartate aminotransferase （AST）, alkaline phosphatase （ALP）, and total bilirubin （TB） were measured. The histopathological examination was carried out to supplement the biochemical results. Results CGA possessed strong anti-oxidative ability in vitro. The CCh-induced liver toxicity experiment showed that the rats pretreated with CGA （300 or 500 mg/kg） had lower levels of ALT, AST, ALP, and TB than those of the CCI4-treated group. These data were supplemented with histopathological examination of rat liver sections. CGA did not show any mortality at the dose up to 5000 mg/kg. Conclusion CGAcould protect the liver againstCCI4-induced oxidative damage in rats, and the possible mechanism of the activity may be due to its free radical-scavenging and anti-oxidative activity.

血必净注射液联合乙酰半胱氨酸对急性百草枯中毒肝肾损伤的作用

目的探讨血必净注射液联合乙酰半胱氨酸(acetylcysteine,AC)对急性百草枯中毒(acute paraquat poisoning,APP)肝肾损伤的作用。方法回顾性分析救治的80例APP患者的临床资料,按治疗方式不同分为AC组(n=39,常规治疗联合AC)、联合组(n=41,在AC组治疗的基础上加用血必净注射液)。比较2组治疗前、治疗2周后呼吸指标[动脉血氧分压(PaO_(2))、氧合指数]、炎症因子水平[白细胞介素-6(interleukin-6,IL-6)、转化生长因子β_(1)(transforming growth factor-β_(1),TGF-β_(1))]和肝肾功能指标[丙氨酸氨基转移酶(glutamic pyruvic transaminase,GPT)、天冬氨酸氨基转移酶(glutamic oxaloacetic transaminase,GOT)、血肌酐(serum creatinine,Scr)和肾小球滤过率(estimated glomerular filtration rate,eGFR)],并观察预后。结果治疗后,2组PaO_(2)、氧合指数和eGFR均较治疗前明显升高(P<0.05),且联合组均明显高于AC组(P<0.05);治疗后,2组血清IL-6、TGF-β_(1)水平和GPT、GOT、Scr均较治疗前明显降低(P<0.05),且联合组均明显低于AC组(P<0.05);联合组1个月内脏器功能衰竭发生率(32.56%vs.56.41%)、病死率(60.98%vs.82.05%)均明显低于AC组(P<0.05)。结论血必净注射液联合AC治疗APP,可明显减轻肝肾损伤,有效抑制炎症反应,显著提高患者的存活率。

青蒿琥酯在脓毒症相关脏器损伤中的保护作用及其机制研究进展

脓毒症是重症监护病房患者死亡的主要原因,其发病机制及病程复杂,严重脓毒症可导致多器官功能障碍综合征,目前暂无有效治疗方法。青蒿琥酯(AS)是青蒿素的衍生物之一,除抗疟疾作用之外还具有抗炎作用,它通过抑制炎症因子释放及调节免疫反应在脓毒症的治疗中发挥明显作用。AS通过调控不同信号通路对脓毒症诱导的急性肺损伤和肝损伤发挥保护作用,对于脓毒症易受累的靶器官如心脏、肾脏、神经系统也具有一定保护作用。本研究总结AS在脓毒症以及脓毒症相关脏器损伤中保护作用的最新研究进展,以期为探索脓毒症相关脏器损伤提供新的研究思路及治疗策略。

Systematic review and meta-analysis: Comparing hepatocellular and cholestatic patterns of drug-induced liver injury

Background and aims:Drug-induced liver injury(DILI)is a leading cause of death from acute liver failure(ALF).Hy's law warns that a hepatocellular pattern of injury accompanied by jaundice and normal alkaline phosphatase(ALP)levels is associated with a 10%or greater chance of progression to transplant or liver-related death.This meta-analysis of DILI studies evaluates acute and chronic outcomes of DILI according to clinical pattern of injury.Methods:We conducted a systematic search using electronic databases PubMed and EMBASE through to 8 March 2022.Our primary outcome was to compare acute outcomes including ALF,liver-related death,and liver transplant between patients experiencing hepatocellular,cholestatic,and mixed patterns of DILI.Our secondary outcome was to compare the rate of DILI chronicity between patients of these three differing patterns of injury.Pooled odds ratios(ORs)and 95%confidence intervals(CIs)were calculated using a random-effects model.Results:Overall,12 studies comprising 4290 patients were included.Patients with cholestatic DILI demonstrated similar rates of ALF(OR:0.80,95%CI:0.46–1.40,p=0.429)and liver-related death(OR:0.92,95%CI:0.50–1.69,p=0.792)compared to patients with hepatocellular DILI.Patients with cholestatic DILI were significantly more likely to experience chronicity compared to patients with hepatocellular DILI(OR:2.53,95%CI:1.34–4.79,p=0.004).

Taking advantage of the potential of mesenchymal stromal cells in liver regeneration:Cells and extracellular vesicles as therapeutic strategies

Cell-based therapies for acute and chronic liver diseases are under continuous progress. Mesenchymal stem/stromal cells(MSCs) are multipotent cells able to migrate selectively to damaged tissue and contribute to its healing and regeneration. The MSC pro-regenerative effect occurs due to their immunomodulatory capacity and their ability to produce factors that promote cell protection and survival. Likewise,it has been observed that part of their paracrine effect is mediated by MSC-derived extracellular vesicles(EVs). EVs contain proteins,lipids and nucleic acids(DNA,m RNA,mi RNA,lnc RNA) from the cell of origin,allowing for intercellular communication. Recently,different studies have demonstrated that MSC-derived EVs could reproduce,at least in part,the biological effects obtained by MSCbased therapies. Moreover,due to EVs' stability for long periods of time and easy isolation methods they have become a therapeutic option to MSCs treatments. This review summarizes the latest results achieved in clinical trials using MSCs as cell therapy for liver regeneration,the role of EVs in liver physiopathology and the potential of MSC-derived EVs as intercellular mediators and therapeutic tools in liver diseases.

Liver injury induced by paracetamol and challenges associated with intentional and unintentional use

Drug induced liver injury(DILI)is a common cause of acute liver injury.Paracetamol,also known as acetaminophen,is a widely used anti-pyretic that has long been established to cause liver toxicity once above therapeutic levels.Hepatotoxicity from paracetamol overdose,whether intentional or nonintentional,is the most common cause of DILI in the United States and remains a global issue.Given the increased prevalence of combination medications in the form of pain relievers and antihistamines,paracetamol can be difficult to identify and remains a significant cause of acute hepatotoxicity,as evidenced by its contribution to over half of all acute liver failure cases in the United States.This is especially concerning given that,when co-ingested with other medications,the rise in serum paracetamol levels may be delayed past the 4-hour post-ingestion mark that is currently used to determine patients that require medical therapy.This review serves to describe the clinical and pathophysiologic features of hepatotoxicity secondary to paracetamol and provide an update on current available knowledge and treatment options.

Liver involvement in the drug reaction,eosinophilia,and systemic symptoms syndrome

First described in 1996,the drug reaction,eosinophilia,and systemic symptoms syndrome(DReSS) is considered,along with Stevens-Johnson syndrome and toxic epidermal necrolysis,a severe cutaneous drug reaction. It is characterized by the presence of a maculopapular erythematous skin eruption,fever,lymphadenopathy,influenza-like symptoms,eosinophilia,and visceral involvement such as hepatitis,pneumonitis,myocarditis,pericarditis,nephritis,and colitis. The prognosis of patients with DReSS is related to the severity of visceral involvement. The mortality ranges from approximately 5% to 10%,and death is mainly due to liver failure,which is also the organ most commonly involved in this syndrome. Although it was previously hypothesized in 1994,DReSS syndrome can lead to reactivation of one or more human herpesvirus family members. Now being included as diagnostic criteria in a proposed diagnostic score system,this reactivation can be detected up to 2-3 wk after DReSS syndrome onset. Other causes of mortality in DReSS syndrome include myocardial or pulmonary lesions and hemophagocytosis. We reviewed the literature of previously reported case-series of DReSS and liver involvement,highlighting the pattern of liver damage,the treatment used,and the outcome.

Role of immune dysfunction in drug induced liver injury

Drug-induced liver injury(DILI)is one of the leading causes of liver failure and withdrawal of drugs from the market.A poor understanding of the precipitating event aetiology and mechanisms of disease progression has rendered the prediction and subsequent treatment intractable.Recent literature suggests that some drugs can alter the liver’s repair systems resulting in injury.The pathophysiology of DILI is complex,and immune dysfunction plays an important role in determining the course and severity of the disease.Immune dysfunction is influenced by the host response to drug toxicity.A deeper understanding of these processes may be beneficial in the management of DILI and aid in drug development.This review provides a structured framework presenting DILI in three progressive stages that summarize the interplay between drugs and the host defence networks.

损伤相关分子模式在慢加急肝衰竭中的研究进展

慢加急肝衰竭(ACLF)是在慢性肝病的基础上,由各种急性触发因素引起的一组与严重急性肝功能损害和多器官功能衰竭有关的临床综合征。由于其病情严重、进展迅速、病死率高,因此越来越受到关注。最近的研究表明,ACLF的发病机制主要包括直接损伤和免疫损伤。在免疫损伤中,损伤相关分子模式(DAMPs)引起的肝内浸润和免疫细胞功能亢进是导致ACLF发生的重要因素。DAMPs可以作为ACLF早期诊断和治疗的生物靶分子,如高迁移率族蛋白1、热休克蛋白等。该文将综述近年来DAMPs与ACLF预后关系研究的进展,参考文献主要通过PubMed和CNKI搜索确定,包括2023年6月之前发布的相关研究,总结了DAMPs作为ACLF预后标志物的文献报告。

CRISPR/Cas9沉默Fas可抑制急性肝衰竭细胞线粒体自噬及减轻线粒体损伤

目的 探讨凋亡相关因子(Fas/CD95)在急性肝衰竭疾病进展中的作用及机制。方法 构建刀豆蛋白A诱导的急性肝衰竭小鼠动物模型,通过透射电子显微镜及免疫印迹检测了急性肝衰竭肝细胞内的线粒体自噬发生;在小鼠尾静脉输注靶向Fas基因的CRISPR/Cas9质粒,随后予以刀豆蛋白A诱发急性肝衰竭,检测小鼠肝组织急性损伤情况及肝细胞内线粒体自噬及线粒体损伤的变化,同时体外转染靶向Fas的CRISPR/Cas质粒到细胞内,刀豆蛋白A诱导HepG2肝细胞损伤,验证Fas敲除后对线粒体自噬和线粒体损伤的影响。结果 刀豆蛋白A可诱导小鼠急性肝衰竭,透射电镜观察发现肝细胞中发生了线粒体自噬,肝细胞内p62蛋白水平降低,PINK1/Parkin的蛋白上调,Fas的表达上调;小鼠肝组织和体外肝细胞先予以PX330Fas质粒转染,再予以刀豆蛋白A诱导肝损伤后,LC3II/LC3I表达比值减低,p62蛋白的表达得到恢复,线粒体蛋白COX4I1和线粒体DNA含量的水平下降,Fas表达下调,与转染空白质粒的对照组相比,差异均有统计学意义。结论 CRISPR/Cas9沉默Fas抑制急性肝衰竭进展及肝细胞内线粒体自噬的发生和线粒体损伤,从而减轻急性肝衰竭的细胞死亡,为临床开展急性肝衰竭的新治疗策略提供了新依据和新靶点。

Preclinical models of idiosyncratic drug-induced liver injury(iDILI):Moving towards prediction

Idiosyncratic drug-induced liver injury(iDILI) encompasses the unexpected harms that prescription and non-prescription drugs,herbal and dietary supplements can cause to the liver.iDILI remains a major public health problem and a major cause of drug attrition.Given the lack of biomarkers for iDILI prediction,diagnosis and prognosis,searching new models to predict and study mechanisms of iDILI is necessary.One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI.Thus,major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients.However,there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms.Therefore,there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug development.Here,the current experimental models and the future directions in iDILI modelling are thoroughly discussed,focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models.We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.