Cirrhosis represents the end stage of chronic liver disease,significantly reducing life expectancy as it progresses from a compensated to a decompensated state,leading to serious complications.Recent improvements in m...Cirrhosis represents the end stage of chronic liver disease,significantly reducing life expectancy as it progresses from a compensated to a decompensated state,leading to serious complications.Recent improvements in medical treatment have created a shift in cirrhosis management.Various causes,including hepatitis viruses,alcohol consumption,and fatty liver disease,contribute to cirrhosis and are closely linked to liver cancer.The disease develops through hepatocyte necrosis and regeneration,resulting in fibrosis and sinusoidal capillarization,leading to portal hypertension and complications such as ascites,hepatic encephalopathy,and organ dysfunction.Cirrhosis also holds an increased risk of hepatocellular carcinoma.Diagnosing cirrhosis involves assessing fibrosis scores through blood tests and measuring liver stiffness through elastography.Liver transplantation is the definitive treatment for endstage liver disease and acute liver failure.展开更多
BACKGROUND Liver transplantation aims to increase the survival of patients with end-stage liver diseases and improve their quality of life.The number of organs available for transplantation is lower than the demand.To...BACKGROUND Liver transplantation aims to increase the survival of patients with end-stage liver diseases and improve their quality of life.The number of organs available for transplantation is lower than the demand.To provide fair organ distribution,predictive mortality scores have been developed.AIM To compare the Acute Physiology and Chronic Health Evaluation IV(APACHE IV),balance of risk(BAR),and model for end-stage liver disease(MELD)scores as predictors of mortality.METHODS Retrospective cohort study,which included 283 adult patients in the postoperative period of deceased donor liver transplantation from 2014 to 2018.RESULTS The transplant recipients were mainly male,with a mean age of 58.1 years.Donors were mostly male,with a mean age of 41.6 years.The median cold ischemia time was 3.1 hours,and the median intensive care unit stay was 5 days.For APACHE IV,a mean of 59.6 was found,BAR 10.7,and MELD 24.2.The 28-day mortality rate was 9.5%,and at 90 days,it was 3.5%.The 28-day mortality prediction for APACHE IV was very good[area under the curve(AUC):0.85,P<0.001,95%CI:0.76-0.94],P<0.001,BAR(AUC:0.70,P<0.001,95%CI:0.58–0.81),and MELD(AUC:0.66,P<0.006,95%CI:0.55-0.78),P<0.008.At 90 days,the data for APACHE IV were very good(AUC:0.80,P<0.001,95%CI:0.71–0.90)and moderate for BAR and MELD,respectively,(AUC:0.66,P<0.004,95%CI:0.55–0.77),(AUC:0.62,P<0.026,95%CI:0.51–0.72).All showed good discrimination between deaths and survivors.As for the best value for liver transplantation,it was significant only for APACHE IV(P<0.001).CONCLUSION The APACHE IV assessment score was more accurate than BAR and MELD in predicting mortality in deceased donor liver transplant recipients.展开更多
Aortic stenosis(AS),a progressive disease affecting aortic valve function,is common among individuals with metabolic and degenerative conditions,and is notably challenging to manage in patients with cirrhosis.Patients...Aortic stenosis(AS),a progressive disease affecting aortic valve function,is common among individuals with metabolic and degenerative conditions,and is notably challenging to manage in patients with cirrhosis.Patients with cirrhosis frequently experience exacerbated AS symptoms due to the hyperdynamic circulatory state induced by portal hypertension,which masks early AS signs,resulting in delayed diagnosis.The coexistence of AS and liver disease significantly complicates management,particularly for those awaiting liver transplantation(LT),where untreated AS can increase perioperative morbidity and mortality.This review examines the pathophysiology,clinical manifestations,and management of AS in cirrhotic patients,with a focus on implications for LT candidates.Available treatment options,including surgical aortic valve replacement and transcatheter aortic valve replacement(TAVR),are discussed,with TAVR emerging as a preferred approach due to favorable outcomes in high-risk patients.We also explore the potential role of TAVR as a bridge to LT,with case reports showing promising,albeit anecdotal,success in restoring LT candidacy.Limitations in current perioperative risk assessment tools,which inadequately address the unique risks faced by cirrhotic patients undergoing cardiac procedures,highlight the need for multi-disciplinary care and further research to improve outcomes of patients with concomitant end-stage liver disease and AS.展开更多
BACKGROUND Single-ventricle congenital heart disease often requires the Fontan procedure,which can lead to Fontan-associated liver disease(FALD)and multi-organ failure.Combined heart-liver transplantation(CHLT)is a po...BACKGROUND Single-ventricle congenital heart disease often requires the Fontan procedure,which can lead to Fontan-associated liver disease(FALD)and multi-organ failure.Combined heart-liver transplantation(CHLT)is a potential lifesaving option for these patients.AIMTo investigate the outcomes and complications of CHLT in patients with failing Fontan physiology.METHODSSeven retrospective studies of 121 patients undergoing CHLT were systematically reviewed. Quality was assessedwith the Newcastle-Ottawa Scale. A meta-analysis using random-effects models to calculate odds ratios (ORs) ormean differences (MDs) with 95% confidence intervals.RESULTSThe pooled 30-day, 1-year, 5-year, and 10-year survival rates after CHLT were 92.6%, 86.78%, 81.17%, and 77.8%,respectively. The mean intensive care unit and total hospital lengths of stay were 8.46 and 28.16 days. Meanischemic time was 267.29 minutes, while cardiopulmonary bypass time was 260.27 minutes. Infections (30%), renalreplacement therapy (36.84%), and graft rejection (12.34%) were notable complications. Compared to orthotopicheart transplantation (OHT), CHLT significantly reduced mortality (OR: 0.30, P = 0.009) and ischemic time (MD:–65.93 minutes), with no major differences in perioperative morbidity.CONCLUSIONCHLT offers a survival advantage over OHT for patients with FALD and failing Fontan physiology. Futureprospective studies are warranted to refine eligibility and improve long-term survival.展开更多
Metabolic dysfunction-associated fatty liver disease(MAFLD)now affects roughly one-quarter of the world’s population,reflecting the global spread of obesity and insulin resistance.Reframing non-alcoholic fatty liver ...Metabolic dysfunction-associated fatty liver disease(MAFLD)now affects roughly one-quarter of the world’s population,reflecting the global spread of obesity and insulin resistance.Reframing non-alcoholic fatty liver disease as MAFLD emphasizes its metabolic roots and spotlights the gut-liver axis,where intestinal dysbiosis acts as a key driver of hepatic injury.Altered microbial com-munities disrupt epithelial integrity,promote bacterial translocation,and trigger endotoxin-mediated inflammation that accelerates steatosis,lipotoxicity,and fibrogenesis.Concurrent shifts in bile acid signaling and short-chain fatty acid profiles further impair glucose and lipid homeostasis,amplifying cardiometabolic risk.Epidemiological studies reveal pervasive dysbiosis in MAFLD cohorts,linked to diet quality,sedentary behavior,adiposity,and host genetics.Newly developed microbiome-derived biomarkers,advanced elastography,and integrated multi-omics panels hold promise for non-invasive diagnosis and stratification,although external validation remains limited.In early trials,interventions that re-engineer the microbiota including tailored pre-/pro-/synbiotics,rational diet patterns,next-generation fecal microbiota transplantation,and bile-acid-modulating drugs show encouraging histological and metabolic gains.Optimal care will likely couple these tools with weight-centered lifestyle programmes in a pre-cision-medicine framework.Key challenges include inter-ethnic variability in microbiome signatures,the absence of consensus treatment algorithms,and regulatory barriers to live biotherapeutics.Rigorous longitudinal studies are required to translate mechanistic insight into durable clinical benefit and improve patient-centered outcome measures.展开更多
Non-alcoholic fatty liver disease(NAFLD),also referred to as metabolic-associated fatty liver disease,is among the most prevalent chronic liver conditions.In some cases,NAFLD may lead to liver inflammation and non-alc...Non-alcoholic fatty liver disease(NAFLD),also referred to as metabolic-associated fatty liver disease,is among the most prevalent chronic liver conditions.In some cases,NAFLD may lead to liver inflammation and non-alcoholic steatohepatitis,which can eventually progress to liver cirrhosis and hepatocellular carcinoma.The pathophysiology of NAFLD is complex,involving both genetic and environmental factors.NAFLD is a multisystem disease linked to a higher likelihood of developing metabolic disorders such as type 2 diabetes,obesity,and cardiovascular and chronic kidney diseases.The gut-liver axis represents a key connection between the gut microbiota and the liver,and its disruption has been linked to NAFLD.Growing evidence underscores the significant role of gut microbiota in the onset and progression of NAFLD,with alterations in the gut microbiome and impaired gut barrier function.Studies have identified key microbiota signatures and metabolites linked to NAFLD,implicating oxidative stress,endotoxemia,and inflammatory pathways that further strengthen the connection between gut microbiota and NAFLD.Modulation of gut microbiota through diet and microbiota-centered therapies,such as next-generation probiotics and fecal microbiota transplantation,holds promise for treating NAFLD.In this review,we explore the key link between gut microbiota and the development and progression of NAFLD,as well as its potential applications in the diagnosis and treatment of the disease.展开更多
Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in m...Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.展开更多
The liver experiences various changes with aging that could affect clinical characteristics and outcomes in patients with liver diseases.Both liver volume and blood flow decrease significantly with age.These changes a...The liver experiences various changes with aging that could affect clinical characteristics and outcomes in patients with liver diseases.Both liver volume and blood flow decrease significantly with age.These changes and decreased cytochrome P450 activity can affect drug metabolism,increasing susceptibility to drug-induced liver injury.Immune responses against pathogens or neoplastic cells are lower in the elderly,although these individuals may be predisposed to autoimmunity through impairment of dendritic cell maturation and reduction of regulatory T cells.These changes in immune functions could alter the pathogenesis of viral hepatitis and autoimmune liver diseases,as well as the development of hepatocellular carcinoma.Moreover,elderly patients have significantly decreased reserve functions of various organs,reducing their tolerability to treatments for liver diseases.Collectively,aged patients show various changes of the liver and other organs that could affect the clinical characteristics and management of liver diseases in these patients.展开更多
Autophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients.The potential role of autophagy in diseas...Autophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients.The potential role of autophagy in disease is increasingly recognised and investigated in the last decade.Nowadays it is commonly accepted that autophagy plays a role in the hepatic lipid metabolism.Hence,dysfunction of autophagy may be an underlying cause of non-alcoholic fatty liver disease.However,controversy of the exact role of autophagy in the lipid metabolism exists:some publications report a lipolytic function of autophagy,whereas others claim a lipogenic function.This review aims to give an update of the present knowledge on autophagy in the hepatic lipid metabolism,hepatic insulin resistance,steatohepatitis and hepatic fibrogenesis.展开更多
This review aims at evaluating the existing evidence regarding post reperfusion syndrome, providing a description of the pathophysiologic mechanisms involved and possible management and preventive strategies. A Pub Me...This review aims at evaluating the existing evidence regarding post reperfusion syndrome, providing a description of the pathophysiologic mechanisms involved and possible management and preventive strategies. A Pub Med search was conducted using the Me SH database, "Reperfusion" AND "liver transplantation" were the combined Me SH headings; EMBASE and the Cochrane library were also searched using the same terms. 52 relevant studies and one ongoing trial were found. The concept of post reperfusion syndrome has evolved through years to a multisystemic disorder. The implications of the main organ, recipient and procedure related factors in the genesis of this complex syndrome are discussed in the text as the novel pharmacologic and technical approaches to reduce its incidence. However the available evidence about risk factors, physiopathology and preventive measures is still confusing, the presence of two main definitions and the numerosity of possible confounding factors greatly complicates the interpretation of the studies.展开更多
Polycystic liver diseases(PLD)represent a group of genetic disorders in which cysts occur in the liver(autosomal dominant polycystic liver disease)or in combination with cysts in the kidneys(autosomal dominant polycys...Polycystic liver diseases(PLD)represent a group of genetic disorders in which cysts occur in the liver(autosomal dominant polycystic liver disease)or in combination with cysts in the kidneys(autosomal dominant polycystic kidney disease).Regardless of the genetic mutations,the natural history of these disorders is alike.The natural history of PLD is characterized by a continuous increase in the volume and the number of cysts.Both genders are affected;however,women have a higher prevalence.Most patients with PLD are asymptomatic and can be managed conservatively.Severe symptoms can affect 20%of patients who develop massive hepatomegaly with compression of the surrounding organs.Rrarely,patients with PLD suffer from acutecomplications caused by the torsion of hepatic cysts,intraluminal cystic hemorrhage and infections.The most common methods for the diagnosis of PLD are cross sectional imaging studies.Abdominal ultrasound and computerized tomography are the two most frequently used investigations.Magnetic resonance imaging is more sensitive and specific,and it is a valuable test for patients with intravenous contrast allergies or renal dysfunction.Different treatment modalities are available to physicians caring for these patients.Medical treatment has been ineffective.Percutaneous sclerotherapy,transarterial embolization,cyst fenestration,hepatic resection and liver transplantation are indicated to specific groups of patients and have to be tailored according to the extent of disease.This review outlines the current knowledge of the pathophysiology,clinical course,diagnosis and treatment strategies of PLD.展开更多
Recent findings in the pathophysiology and monitoring of hemostasis in patients with end stage liver disease have major impact on coagulation management during liver transplantation. There is increasing evidence, that...Recent findings in the pathophysiology and monitoring of hemostasis in patients with end stage liver disease have major impact on coagulation management during liver transplantation. There is increasing evidence, that the changes in both coagulation factors and platelet count regularly observed in patients with liver cirrhosis cannot be interpreted as a reliable indicator of diffuse bleeding risk. Instead, a differentiated view on hemostasis has led to the concept of a rebalanced coagulation system: While it is important to recognize that procoagulant factors are reduced in liver cirrhosis, it is also evident that synthesis of anticoagulant factors and fibrinolytic proteins produced in the liver is also diminished. Similarly, the decreased platelet count may be counterbalanced by increased platelet aggregability caused by highly active von Willebrand multimeres. The coagulation system is therefor stated to be rebalanced. While under normal "unstressed" conditions diffuse bleeding is rarely observed, however both diffuse bleeding or thrombus formation may occur when compensation mechanisms are exhausted. While most patients presenting for liver transplantation have severe cirrhosis, liver function and thus production of pro- and anticoagulant factors can be preserved especially in cholestatic liver disease. During liver transplantation, profound changes in the hemostasis system can occur. Surgical bleeding can lead to diffuse bleeding as coagulation factors and platelets are already reduced. Ischemia and tissue trauma can lead to alterations of hemostasis comparable to trauma induced coagulopathy. A further common disturbance often starting with the reperfusion of the transplanted organ is hyperfibrinolysis which can eventually precipitate complete consumption of fibrinogen and an endogenous heparinization by glycocalyx shedding. Moreover, thrombotic events inliver transplantations are not uncommon and contribute to increased mortality. Besides conventional laboratory methods, bed-side monitoring of hemostasis(e.g., thrombelastography, thrombelastometry) is often used during liver transplantation to rapidly diagnose decreases in fibrinogen and platelet count as well as hyperfibrinolysis and to guide treatment with blood products, factor concentrates, and antifibrinolytics. There is also evidence which suggests when algorithms based on bed-side hemostasis monitoring are used a reduction of blood loss, blood product use, and eventual mortality are possible. Notably, the bed-side monitoring of anticoagulant pathways and the thrombotic risk is not possible at time and thus a cautious and restrictive use of blood products is recommended.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
BACKGROUND: CT perfusion has been reported to have great advantages in detecting hepatic diseases. However, currently there are no studies showing the potential value of multi-slice CT perfusion with the deconvolution...BACKGROUND: CT perfusion has been reported to have great advantages in detecting hepatic diseases. However, currently there are no studies showing the potential value of multi-slice CT perfusion with the deconvolution model method in diagnosing early hemodynamic changes caused by liver tumors. This study was undertaken to determine if early hemodynamic changes caused by liver tumors can be depicted with the perfusion imaging of multi-slice CT. METHODS: Ten New Zealand white rabbits before and after VX2 liver tumor inoculation served as the experimental animals. Ten normal rabbits served as controls. All underwent multi-slice CT perfusion for the measurement of hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS) and hepatic artery index (HAI). RESULTS: With the exception of MTT, which decreased significantly at the tumor periphery, HBF, HBV,. PS and HAI increased significantly compared with the surrounding normal tissue. All these changes occurred at days 5-9 after tumor inoculation. Statistically significant changes in these values were detected with tumor growth. CONCLUSIONS: The hemodynamic changes in the liver caused by rabbit VX2 liver tumor can be detected after tumor inoculation, and functional CT can evaluate the physiological characteristics of early tumor angiogenesis.展开更多
Background:Since the first success in an adult patient,living donor liver transplantation(LDLT)has become an universally used procedure.Small-for-size syndrome(SFSS)is a well-known complication after partial LT,especi...Background:Since the first success in an adult patient,living donor liver transplantation(LDLT)has become an universally used procedure.Small-for-size syndrome(SFSS)is a well-known complication after partial LT,especially in cases of adult-to-adult LDLT.The definition of SFSS slightly varies among transplant physicians.The use of a partial liver graft has risks of SFSS development.Persistent portal vein(PV)hypertension and PV hyper-perfusion after LT were identified as the main factors.Hence,various approaches were explored to modulate PV flow and decrease PV pressure in order to alleviate this syndrome.Herein,the definition,clinical symptoms,pathophysiology,basic research,as well as preventive and treatment strategies for SFSS are reviewed based on an extensive review of the literature and on our own experiences.Data sources:The articles were collected through PubMed using search terms“liver transplantation”,“living donor liver transplantation”,“living liver donation”,“partial graft”,“small-for-size graft”,“small-forsize syndrome”,“graft volume”,“remnant liver”,“standard liver volume”,“graft to recipient body weight ratio”,“sarcopenia”,“porcine”,“swine”,and“rat”.English publications published before March 31,2020 were included in this review.Results:Many transplant surgeons performed PV flow modulation,including portocaval shunt,splenic artery ligation and splenectomy.With these techniques,patient outcome has been improved even when using a"small"graft.Other factors,such as preoperative recipients’nutritional and skeletal muscle status,graft congestion,and donor factors,were also identified as risk factors which all have been addressed using various strategies.Conclusions:The surgical approach controlling PV flow and pressure could help to prevent SFSS especially in severely ill recipients.In the absence of efficacious medications to resolve SFSS,conservative treatments,including aggressive fluid balance correction for massive ascites,anti-microbiological therapy to prevent or control sepsis and intensive nutritional therapy,are all required if SFSS could not be prevented.展开更多
Autophagy is a highly conserved intracellular degradation pathway by which bulk cytoplasm and superfluous or damaged organelles are enveloped by double membrane structures termed autophagosomes. The autophago-somes th...Autophagy is a highly conserved intracellular degradation pathway by which bulk cytoplasm and superfluous or damaged organelles are enveloped by double membrane structures termed autophagosomes. The autophago-somes then fuse with lysosomes for degradation of their contents, and the resulting amino acids can then recycle back to the cytosol. Autophagy is normally activated in response to nutrient deprivation and other stressors and occurs in all eukaryotes. In addition to maintaining energy and nutrient balance in the liver, it is now clear that autophagy plays a role in liver protein aggregates related diseases, hepatocyte cell death, steatohepatitis, hepatitis virus infection and hepatocellular carcinoma. In this review, I discuss the recent findings of autophagy with a focus on its role in liver pathophysiology.展开更多
Classically, the non-alcoholic fatty liver disease(NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of hyperinsulinemia and insulin resi...Classically, the non-alcoholic fatty liver disease(NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of hyperinsulinemia and insulin resistance, accompanying obesity, that leads to liver steatosis increasing the absolute non esterified fatty acids uptake in the liver and the esterification to form triacylglycerol. The oxidative stress is involved in the second hit leading to the progression to nonalcoholic steatohepatitis(NASH) because of its harmful action on steatosic hepatocytes. However, at the present time, the two hits hypothesis needs to be updated because of the discover of genetic polymorphisms involved both in the liver fat accumulation and progression to NASH that make more intriguing understanding the NAFLD pathophysiological mechanisms. In this editorial, we want to underline the role of PNPLA3 I148 M, GPR120 R270 H and TM6SF2 E167 K in the pediatric NAFLD development because they add new pieces to the comprehension of the NAFLD pathophysiological puzzle. The PNPLA3 I148 M polymorphism encodes for an abnormal protein which predisposes to intrahepatic triglycerides accumulation both for a loss-of-function of its triglyceride hydrolase activity and for a gain-of-function of its lipogenic activity.Therefore, it is involved in the first hit, such as TM6SF2 E167 K polymorphisms that lead to intrahepatic fat accumulation through a reduced very low density lipoprotein secretion. On the other hand, the GPR120 R270 H variant, reducing the anti-inflammatory action of the GPR120 receptor expressed by Kuppfer cells, is involved in the second hit leading to the liver injury.展开更多
Cerebral oedema is a devastating consequence of acute liver failure(ALF)and may be associated with the development of intracranial hypertension and death.In ALF,some patients may develop cerebral oedema and increased ...Cerebral oedema is a devastating consequence of acute liver failure(ALF)and may be associated with the development of intracranial hypertension and death.In ALF,some patients may develop cerebral oedema and increased intracranial pressure but progression to lifethreatening intracranial hypertension is less frequent than previously described,complicating less than one third of cases who have proceeded to coma since the advent of improved clinical care.The rapid onset of encephalopathy may be dramatic with the development of asterixis,delirium,seizures and coma.Cytotoxic and vasogenic oedema mechanisms have been implicated with a preponderance of experimental data favouring a cytotoxic mechanism.Astrocyte swelling is the most consistent neuropathological finding in humans with ALF and ammonia plays a definitive role in the development of cytotoxic brain oedema.The mechanism(s)by which ammonia induces astrocyte swelling remains unclear but glutamine accumulation within astrocytes has led to the osmolyte hypothesis.Current evidence also supports an alternate‘Trojan horse’hypothesis,with glutamine as a carrier of ammonia into mitochondria,where its accumulation results in oxidative stress,energy failure and ultimately astrocyte swelling.Although a complete breakdown of the blood-brain barrier is not evident in human ALF,increased permeation to water and other small molecules such as ammonia has been demonstrated resulting from subtle alterations in the protein composition of paracellular tight junctions.At present,there is no fully efficacious therapy for cerebral oedema other than liver transplantation and this reflects our incomplete knowledge of the precise mechanisms underlying this process which remain largely unknown.展开更多
Liver fibrosis is a complex pathological process controlled by a variety of cells,mediators and signaling pathways.Hepatic stellate cells play a central role in the development of liver fibrosis.In chronic liver disea...Liver fibrosis is a complex pathological process controlled by a variety of cells,mediators and signaling pathways.Hepatic stellate cells play a central role in the development of liver fibrosis.In chronic liver disease,hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties.This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis.They enter the cell cycle under the influence of various triggers.The“Initiation”phase of hepatic stellate cells activation overlaps and continues with the“Perpetuation”phase,which is characterized by a pronounced inflammatory and fibrogenic reaction.This is followed by a resolution phase if the injury subsides.Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis.In this respect,impairments in intracellular signaling,epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells.Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging,apoptosis,and/or clearance by immune cells,and serve as potential antifibrotic therapy.It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.展开更多
Toll-like receptors(TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated mole...Toll-like receptors(TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte(i.e., hepatocellular injury and regeneration) or hepatic stellate cell(i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases.展开更多
文摘Cirrhosis represents the end stage of chronic liver disease,significantly reducing life expectancy as it progresses from a compensated to a decompensated state,leading to serious complications.Recent improvements in medical treatment have created a shift in cirrhosis management.Various causes,including hepatitis viruses,alcohol consumption,and fatty liver disease,contribute to cirrhosis and are closely linked to liver cancer.The disease develops through hepatocyte necrosis and regeneration,resulting in fibrosis and sinusoidal capillarization,leading to portal hypertension and complications such as ascites,hepatic encephalopathy,and organ dysfunction.Cirrhosis also holds an increased risk of hepatocellular carcinoma.Diagnosing cirrhosis involves assessing fibrosis scores through blood tests and measuring liver stiffness through elastography.Liver transplantation is the definitive treatment for endstage liver disease and acute liver failure.
文摘BACKGROUND Liver transplantation aims to increase the survival of patients with end-stage liver diseases and improve their quality of life.The number of organs available for transplantation is lower than the demand.To provide fair organ distribution,predictive mortality scores have been developed.AIM To compare the Acute Physiology and Chronic Health Evaluation IV(APACHE IV),balance of risk(BAR),and model for end-stage liver disease(MELD)scores as predictors of mortality.METHODS Retrospective cohort study,which included 283 adult patients in the postoperative period of deceased donor liver transplantation from 2014 to 2018.RESULTS The transplant recipients were mainly male,with a mean age of 58.1 years.Donors were mostly male,with a mean age of 41.6 years.The median cold ischemia time was 3.1 hours,and the median intensive care unit stay was 5 days.For APACHE IV,a mean of 59.6 was found,BAR 10.7,and MELD 24.2.The 28-day mortality rate was 9.5%,and at 90 days,it was 3.5%.The 28-day mortality prediction for APACHE IV was very good[area under the curve(AUC):0.85,P<0.001,95%CI:0.76-0.94],P<0.001,BAR(AUC:0.70,P<0.001,95%CI:0.58–0.81),and MELD(AUC:0.66,P<0.006,95%CI:0.55-0.78),P<0.008.At 90 days,the data for APACHE IV were very good(AUC:0.80,P<0.001,95%CI:0.71–0.90)and moderate for BAR and MELD,respectively,(AUC:0.66,P<0.004,95%CI:0.55–0.77),(AUC:0.62,P<0.026,95%CI:0.51–0.72).All showed good discrimination between deaths and survivors.As for the best value for liver transplantation,it was significant only for APACHE IV(P<0.001).CONCLUSION The APACHE IV assessment score was more accurate than BAR and MELD in predicting mortality in deceased donor liver transplant recipients.
文摘Aortic stenosis(AS),a progressive disease affecting aortic valve function,is common among individuals with metabolic and degenerative conditions,and is notably challenging to manage in patients with cirrhosis.Patients with cirrhosis frequently experience exacerbated AS symptoms due to the hyperdynamic circulatory state induced by portal hypertension,which masks early AS signs,resulting in delayed diagnosis.The coexistence of AS and liver disease significantly complicates management,particularly for those awaiting liver transplantation(LT),where untreated AS can increase perioperative morbidity and mortality.This review examines the pathophysiology,clinical manifestations,and management of AS in cirrhotic patients,with a focus on implications for LT candidates.Available treatment options,including surgical aortic valve replacement and transcatheter aortic valve replacement(TAVR),are discussed,with TAVR emerging as a preferred approach due to favorable outcomes in high-risk patients.We also explore the potential role of TAVR as a bridge to LT,with case reports showing promising,albeit anecdotal,success in restoring LT candidacy.Limitations in current perioperative risk assessment tools,which inadequately address the unique risks faced by cirrhotic patients undergoing cardiac procedures,highlight the need for multi-disciplinary care and further research to improve outcomes of patients with concomitant end-stage liver disease and AS.
文摘BACKGROUND Single-ventricle congenital heart disease often requires the Fontan procedure,which can lead to Fontan-associated liver disease(FALD)and multi-organ failure.Combined heart-liver transplantation(CHLT)is a potential lifesaving option for these patients.AIMTo investigate the outcomes and complications of CHLT in patients with failing Fontan physiology.METHODSSeven retrospective studies of 121 patients undergoing CHLT were systematically reviewed. Quality was assessedwith the Newcastle-Ottawa Scale. A meta-analysis using random-effects models to calculate odds ratios (ORs) ormean differences (MDs) with 95% confidence intervals.RESULTSThe pooled 30-day, 1-year, 5-year, and 10-year survival rates after CHLT were 92.6%, 86.78%, 81.17%, and 77.8%,respectively. The mean intensive care unit and total hospital lengths of stay were 8.46 and 28.16 days. Meanischemic time was 267.29 minutes, while cardiopulmonary bypass time was 260.27 minutes. Infections (30%), renalreplacement therapy (36.84%), and graft rejection (12.34%) were notable complications. Compared to orthotopicheart transplantation (OHT), CHLT significantly reduced mortality (OR: 0.30, P = 0.009) and ischemic time (MD:–65.93 minutes), with no major differences in perioperative morbidity.CONCLUSIONCHLT offers a survival advantage over OHT for patients with FALD and failing Fontan physiology. Futureprospective studies are warranted to refine eligibility and improve long-term survival.
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD)now affects roughly one-quarter of the world’s population,reflecting the global spread of obesity and insulin resistance.Reframing non-alcoholic fatty liver disease as MAFLD emphasizes its metabolic roots and spotlights the gut-liver axis,where intestinal dysbiosis acts as a key driver of hepatic injury.Altered microbial com-munities disrupt epithelial integrity,promote bacterial translocation,and trigger endotoxin-mediated inflammation that accelerates steatosis,lipotoxicity,and fibrogenesis.Concurrent shifts in bile acid signaling and short-chain fatty acid profiles further impair glucose and lipid homeostasis,amplifying cardiometabolic risk.Epidemiological studies reveal pervasive dysbiosis in MAFLD cohorts,linked to diet quality,sedentary behavior,adiposity,and host genetics.Newly developed microbiome-derived biomarkers,advanced elastography,and integrated multi-omics panels hold promise for non-invasive diagnosis and stratification,although external validation remains limited.In early trials,interventions that re-engineer the microbiota including tailored pre-/pro-/synbiotics,rational diet patterns,next-generation fecal microbiota transplantation,and bile-acid-modulating drugs show encouraging histological and metabolic gains.Optimal care will likely couple these tools with weight-centered lifestyle programmes in a pre-cision-medicine framework.Key challenges include inter-ethnic variability in microbiome signatures,the absence of consensus treatment algorithms,and regulatory barriers to live biotherapeutics.Rigorous longitudinal studies are required to translate mechanistic insight into durable clinical benefit and improve patient-centered outcome measures.
文摘Non-alcoholic fatty liver disease(NAFLD),also referred to as metabolic-associated fatty liver disease,is among the most prevalent chronic liver conditions.In some cases,NAFLD may lead to liver inflammation and non-alcoholic steatohepatitis,which can eventually progress to liver cirrhosis and hepatocellular carcinoma.The pathophysiology of NAFLD is complex,involving both genetic and environmental factors.NAFLD is a multisystem disease linked to a higher likelihood of developing metabolic disorders such as type 2 diabetes,obesity,and cardiovascular and chronic kidney diseases.The gut-liver axis represents a key connection between the gut microbiota and the liver,and its disruption has been linked to NAFLD.Growing evidence underscores the significant role of gut microbiota in the onset and progression of NAFLD,with alterations in the gut microbiome and impaired gut barrier function.Studies have identified key microbiota signatures and metabolites linked to NAFLD,implicating oxidative stress,endotoxemia,and inflammatory pathways that further strengthen the connection between gut microbiota and NAFLD.Modulation of gut microbiota through diet and microbiota-centered therapies,such as next-generation probiotics and fecal microbiota transplantation,holds promise for treating NAFLD.In this review,we explore the key link between gut microbiota and the development and progression of NAFLD,as well as its potential applications in the diagnosis and treatment of the disease.
基金supported by the National Science Foundation of China(No.82405004,82474253)the Natural Science Foundation postdoctoral project of Chongqing(CSTB2022NSCQ-BHX0709)+2 种基金Chongqing Wanzhou District doctoral“through train”scientific research project(wzstc-20220124)Natural Science Foundation of Chongqing,China(No.Cstc2021jcyj-msxmX0996)Chongqing Wanzhou District Science and Health Joint Medical Research Project(wzstc-kw2023032)。
文摘Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.
文摘The liver experiences various changes with aging that could affect clinical characteristics and outcomes in patients with liver diseases.Both liver volume and blood flow decrease significantly with age.These changes and decreased cytochrome P450 activity can affect drug metabolism,increasing susceptibility to drug-induced liver injury.Immune responses against pathogens or neoplastic cells are lower in the elderly,although these individuals may be predisposed to autoimmunity through impairment of dendritic cell maturation and reduction of regulatory T cells.These changes in immune functions could alter the pathogenesis of viral hepatitis and autoimmune liver diseases,as well as the development of hepatocellular carcinoma.Moreover,elderly patients have significantly decreased reserve functions of various organs,reducing their tolerability to treatments for liver diseases.Collectively,aged patients show various changes of the liver and other organs that could affect the clinical characteristics and management of liver diseases in these patients.
基金Supported by Fund for Scientific Research(FWO)-Flanders(11J9513N,G007412N,G044312N,1802514N),to Kwanten WJ,Martinet W and Francque SM
文摘Autophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients.The potential role of autophagy in disease is increasingly recognised and investigated in the last decade.Nowadays it is commonly accepted that autophagy plays a role in the hepatic lipid metabolism.Hence,dysfunction of autophagy may be an underlying cause of non-alcoholic fatty liver disease.However,controversy of the exact role of autophagy in the lipid metabolism exists:some publications report a lipolytic function of autophagy,whereas others claim a lipogenic function.This review aims to give an update of the present knowledge on autophagy in the hepatic lipid metabolism,hepatic insulin resistance,steatohepatitis and hepatic fibrogenesis.
基金Supported by The Department of Anesthesiology of the University of Bologna
文摘This review aims at evaluating the existing evidence regarding post reperfusion syndrome, providing a description of the pathophysiologic mechanisms involved and possible management and preventive strategies. A Pub Med search was conducted using the Me SH database, "Reperfusion" AND "liver transplantation" were the combined Me SH headings; EMBASE and the Cochrane library were also searched using the same terms. 52 relevant studies and one ongoing trial were found. The concept of post reperfusion syndrome has evolved through years to a multisystemic disorder. The implications of the main organ, recipient and procedure related factors in the genesis of this complex syndrome are discussed in the text as the novel pharmacologic and technical approaches to reduce its incidence. However the available evidence about risk factors, physiopathology and preventive measures is still confusing, the presence of two main definitions and the numerosity of possible confounding factors greatly complicates the interpretation of the studies.
文摘Polycystic liver diseases(PLD)represent a group of genetic disorders in which cysts occur in the liver(autosomal dominant polycystic liver disease)or in combination with cysts in the kidneys(autosomal dominant polycystic kidney disease).Regardless of the genetic mutations,the natural history of these disorders is alike.The natural history of PLD is characterized by a continuous increase in the volume and the number of cysts.Both genders are affected;however,women have a higher prevalence.Most patients with PLD are asymptomatic and can be managed conservatively.Severe symptoms can affect 20%of patients who develop massive hepatomegaly with compression of the surrounding organs.Rrarely,patients with PLD suffer from acutecomplications caused by the torsion of hepatic cysts,intraluminal cystic hemorrhage and infections.The most common methods for the diagnosis of PLD are cross sectional imaging studies.Abdominal ultrasound and computerized tomography are the two most frequently used investigations.Magnetic resonance imaging is more sensitive and specific,and it is a valuable test for patients with intravenous contrast allergies or renal dysfunction.Different treatment modalities are available to physicians caring for these patients.Medical treatment has been ineffective.Percutaneous sclerotherapy,transarterial embolization,cyst fenestration,hepatic resection and liver transplantation are indicated to specific groups of patients and have to be tailored according to the extent of disease.This review outlines the current knowledge of the pathophysiology,clinical course,diagnosis and treatment strategies of PLD.
文摘Recent findings in the pathophysiology and monitoring of hemostasis in patients with end stage liver disease have major impact on coagulation management during liver transplantation. There is increasing evidence, that the changes in both coagulation factors and platelet count regularly observed in patients with liver cirrhosis cannot be interpreted as a reliable indicator of diffuse bleeding risk. Instead, a differentiated view on hemostasis has led to the concept of a rebalanced coagulation system: While it is important to recognize that procoagulant factors are reduced in liver cirrhosis, it is also evident that synthesis of anticoagulant factors and fibrinolytic proteins produced in the liver is also diminished. Similarly, the decreased platelet count may be counterbalanced by increased platelet aggregability caused by highly active von Willebrand multimeres. The coagulation system is therefor stated to be rebalanced. While under normal "unstressed" conditions diffuse bleeding is rarely observed, however both diffuse bleeding or thrombus formation may occur when compensation mechanisms are exhausted. While most patients presenting for liver transplantation have severe cirrhosis, liver function and thus production of pro- and anticoagulant factors can be preserved especially in cholestatic liver disease. During liver transplantation, profound changes in the hemostasis system can occur. Surgical bleeding can lead to diffuse bleeding as coagulation factors and platelets are already reduced. Ischemia and tissue trauma can lead to alterations of hemostasis comparable to trauma induced coagulopathy. A further common disturbance often starting with the reperfusion of the transplanted organ is hyperfibrinolysis which can eventually precipitate complete consumption of fibrinogen and an endogenous heparinization by glycocalyx shedding. Moreover, thrombotic events inliver transplantations are not uncommon and contribute to increased mortality. Besides conventional laboratory methods, bed-side monitoring of hemostasis(e.g., thrombelastography, thrombelastometry) is often used during liver transplantation to rapidly diagnose decreases in fibrinogen and platelet count as well as hyperfibrinolysis and to guide treatment with blood products, factor concentrates, and antifibrinolytics. There is also evidence which suggests when algorithms based on bed-side hemostasis monitoring are used a reduction of blood loss, blood product use, and eventual mortality are possible. Notably, the bed-side monitoring of anticoagulant pathways and the thrombotic risk is not possible at time and thus a cautious and restrictive use of blood products is recommended.
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grants from the Natural Science Foundation of Heilongjiang(D2006-07)the Heilongjiang Educational Committee(1511181).
文摘BACKGROUND: CT perfusion has been reported to have great advantages in detecting hepatic diseases. However, currently there are no studies showing the potential value of multi-slice CT perfusion with the deconvolution model method in diagnosing early hemodynamic changes caused by liver tumors. This study was undertaken to determine if early hemodynamic changes caused by liver tumors can be depicted with the perfusion imaging of multi-slice CT. METHODS: Ten New Zealand white rabbits before and after VX2 liver tumor inoculation served as the experimental animals. Ten normal rabbits served as controls. All underwent multi-slice CT perfusion for the measurement of hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS) and hepatic artery index (HAI). RESULTS: With the exception of MTT, which decreased significantly at the tumor periphery, HBF, HBV,. PS and HAI increased significantly compared with the surrounding normal tissue. All these changes occurred at days 5-9 after tumor inoculation. Statistically significant changes in these values were detected with tumor growth. CONCLUSIONS: The hemodynamic changes in the liver caused by rabbit VX2 liver tumor can be detected after tumor inoculation, and functional CT can evaluate the physiological characteristics of early tumor angiogenesis.
文摘Background:Since the first success in an adult patient,living donor liver transplantation(LDLT)has become an universally used procedure.Small-for-size syndrome(SFSS)is a well-known complication after partial LT,especially in cases of adult-to-adult LDLT.The definition of SFSS slightly varies among transplant physicians.The use of a partial liver graft has risks of SFSS development.Persistent portal vein(PV)hypertension and PV hyper-perfusion after LT were identified as the main factors.Hence,various approaches were explored to modulate PV flow and decrease PV pressure in order to alleviate this syndrome.Herein,the definition,clinical symptoms,pathophysiology,basic research,as well as preventive and treatment strategies for SFSS are reviewed based on an extensive review of the literature and on our own experiences.Data sources:The articles were collected through PubMed using search terms“liver transplantation”,“living donor liver transplantation”,“living liver donation”,“partial graft”,“small-for-size graft”,“small-forsize syndrome”,“graft volume”,“remnant liver”,“standard liver volume”,“graft to recipient body weight ratio”,“sarcopenia”,“porcine”,“swine”,and“rat”.English publications published before March 31,2020 were included in this review.Results:Many transplant surgeons performed PV flow modulation,including portocaval shunt,splenic artery ligation and splenectomy.With these techniques,patient outcome has been improved even when using a"small"graft.Other factors,such as preoperative recipients’nutritional and skeletal muscle status,graft congestion,and donor factors,were also identified as risk factors which all have been addressed using various strategies.Conclusions:The surgical approach controlling PV flow and pressure could help to prevent SFSS especially in severely ill recipients.In the absence of efficacious medications to resolve SFSS,conservative treatments,including aggressive fluid balance correction for massive ascites,anti-microbiological therapy to prevent or control sepsis and intensive nutritional therapy,are all required if SFSS could not be prevented.
基金Supported by NIH R21 AA017421& P20 RR021940& P20 RR016475 from the INBRE program of the National Center for Research Resources (Ding WX)
文摘Autophagy is a highly conserved intracellular degradation pathway by which bulk cytoplasm and superfluous or damaged organelles are enveloped by double membrane structures termed autophagosomes. The autophago-somes then fuse with lysosomes for degradation of their contents, and the resulting amino acids can then recycle back to the cytosol. Autophagy is normally activated in response to nutrient deprivation and other stressors and occurs in all eukaryotes. In addition to maintaining energy and nutrient balance in the liver, it is now clear that autophagy plays a role in liver protein aggregates related diseases, hepatocyte cell death, steatohepatitis, hepatitis virus infection and hepatocellular carcinoma. In this review, I discuss the recent findings of autophagy with a focus on its role in liver pathophysiology.
文摘Classically, the non-alcoholic fatty liver disease(NAFLD) physiopathology and progression has been summarized in the two hits hypothesis. The first hit is represented by the action of hyperinsulinemia and insulin resistance, accompanying obesity, that leads to liver steatosis increasing the absolute non esterified fatty acids uptake in the liver and the esterification to form triacylglycerol. The oxidative stress is involved in the second hit leading to the progression to nonalcoholic steatohepatitis(NASH) because of its harmful action on steatosic hepatocytes. However, at the present time, the two hits hypothesis needs to be updated because of the discover of genetic polymorphisms involved both in the liver fat accumulation and progression to NASH that make more intriguing understanding the NAFLD pathophysiological mechanisms. In this editorial, we want to underline the role of PNPLA3 I148 M, GPR120 R270 H and TM6SF2 E167 K in the pediatric NAFLD development because they add new pieces to the comprehension of the NAFLD pathophysiological puzzle. The PNPLA3 I148 M polymorphism encodes for an abnormal protein which predisposes to intrahepatic triglycerides accumulation both for a loss-of-function of its triglyceride hydrolase activity and for a gain-of-function of its lipogenic activity.Therefore, it is involved in the first hit, such as TM6SF2 E167 K polymorphisms that lead to intrahepatic fat accumulation through a reduced very low density lipoprotein secretion. On the other hand, the GPR120 R270 H variant, reducing the anti-inflammatory action of the GPR120 receptor expressed by Kuppfer cells, is involved in the second hit leading to the liver injury.
基金Supported by Medical Research Council(MRC)Centre for Transplantation,King’s College London,United Kingdom-MRC grant No.MR/J006742/1The National Institute for Health Research(NIHR)Biomedical Research Centre based at Guy’s and St Thomas’NHS Foundation Trust and King’s College London
文摘Cerebral oedema is a devastating consequence of acute liver failure(ALF)and may be associated with the development of intracranial hypertension and death.In ALF,some patients may develop cerebral oedema and increased intracranial pressure but progression to lifethreatening intracranial hypertension is less frequent than previously described,complicating less than one third of cases who have proceeded to coma since the advent of improved clinical care.The rapid onset of encephalopathy may be dramatic with the development of asterixis,delirium,seizures and coma.Cytotoxic and vasogenic oedema mechanisms have been implicated with a preponderance of experimental data favouring a cytotoxic mechanism.Astrocyte swelling is the most consistent neuropathological finding in humans with ALF and ammonia plays a definitive role in the development of cytotoxic brain oedema.The mechanism(s)by which ammonia induces astrocyte swelling remains unclear but glutamine accumulation within astrocytes has led to the osmolyte hypothesis.Current evidence also supports an alternate‘Trojan horse’hypothesis,with glutamine as a carrier of ammonia into mitochondria,where its accumulation results in oxidative stress,energy failure and ultimately astrocyte swelling.Although a complete breakdown of the blood-brain barrier is not evident in human ALF,increased permeation to water and other small molecules such as ammonia has been demonstrated resulting from subtle alterations in the protein composition of paracellular tight junctions.At present,there is no fully efficacious therapy for cerebral oedema other than liver transplantation and this reflects our incomplete knowledge of the precise mechanisms underlying this process which remain largely unknown.
文摘Liver fibrosis is a complex pathological process controlled by a variety of cells,mediators and signaling pathways.Hepatic stellate cells play a central role in the development of liver fibrosis.In chronic liver disease,hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties.This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis.They enter the cell cycle under the influence of various triggers.The“Initiation”phase of hepatic stellate cells activation overlaps and continues with the“Perpetuation”phase,which is characterized by a pronounced inflammatory and fibrogenic reaction.This is followed by a resolution phase if the injury subsides.Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis.In this respect,impairments in intracellular signaling,epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells.Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging,apoptosis,and/or clearance by immune cells,and serve as potential antifibrotic therapy.It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.
文摘Toll-like receptors(TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte(i.e., hepatocellular injury and regeneration) or hepatic stellate cell(i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases.
