Novel Time-dependent Multi-omics Integration in Sepsis-associated Liver Dysfunction

The recently developed technologies that allow the analysis of each single omics have provided an unbiased insight into ongoing disease processes.However,it remains challenging to specify the study design for the subsequent integration strategies that can associate sepsis pathophysiology and clinical outcomes.Here,we conducted a time-dependent multi-omics integration(TDMI)in a sepsis-associated liver dysfunction(SALD)model.We successfully deduced the relation of the Toll-like receptor 4(TLR4)pathway with SALD.Although TLR4 is a critical factor in sepsis progression,it is not specified in single-omics analyses but only in the TDMI analysis.This finding indicates that the TDMI-based approach is more advantageous than single-omics analyses in terms of exploring the underlying pathophysiological mechanism of SALD.Furthermore,TDMI-based approach can be an ideal paradigm for insightful biological interpretations of multi-omics datasets that will potentially reveal novel insights into basic biology,health,and diseases,thus allowing the identification of promising candidates for therapeutic strategies.

Interplay between metabolic dysfunction-associated fatty liver disease and renal function: An intriguing pediatric perspective

Over recent years,the nomenclature of non-alcoholic fatty liver disease has undergone significant changes.Indeed,in 2020,an expert consensus panel proposed the term“Metabolic(dysfunction)associated fatty liver disease”(MAFLD)to underscore the close association of fatty liver with metabolic abnormalities,thereby highlighting the cardiometabolic risks(such as metabolic syndrome,type 2 diabetes,insulin resistance,and cardiovascular disease)faced by these patients since childhood.More recently,this term has been further replaced with metabolic associated steatotic liver disease.It is worth noting that emerging evidence not only supports a close and independent association of MAFLD with chronic kidney disease in adults but also indicates its interplay with metabolic impairments.However,comparable pediatric data remain limited.Given the progressive and chronic nature of both diseases and their prognostic cardiometabolic implications,this editorial aims to provide a pediatric perspective on the intriguing relationship between MAFLD and renal function in childhood.

Metabolic dysfunction-associated fatty liver disease and low muscle strength: A comment

The diagnosis of non-alcoholic fatty liver disease(NAFLD)and metabolic dysfunction-associated fatty liver disease only on the basis of laboratory parameter score such as Hepatic Steatosis Index which includes liver enzymes,gender,basal metabolic index,and presence of diabetic mellitus is not sufficient to exclude other causes of deranged liver enzymes especially medications and autoimmune related liver diseases.As the guideline suggests ultrasound is the preferred first-line diagnostic procedure for imaging of NAFLD,as it provides additional diagnostic information and the combination of biomarkers/scores and transient elastography might confer additional diagnostic accuracy and evident from previous similar studies too.

Metabolic dysfunction-associated steatotic liver disease:A silent pandemic

The worldwide epidemiology of non-alcoholic fatty liver disease(NAFLD)is showing an upward trend,parallel to the rising trend of metabolic syndrome,owing to lifestyle changes.The pathogenesis of NAFLD has not been fully understood yet.Therefore,NAFLD has emerged as a public health concern in the field of hepatology and metabolisms worldwide.Recent changes in the nomenclature from NAFLD to metabolic dysfunction-associated steatotic liver disease have brought a positive outlook changes in the understanding of the disease process and doctor-patient communication.Lifestyle changes are the main treatment modality.Recently,clinical trial using drugs that target‘insulin resistance’which is the driving force behind NAFLD,have shown promising results.Further translational research is needed to better understand the underlying pathophysiological mechanism of NAFLD which may open newer avenues of therapeutic targets.The role of gut dysbiosis in etiopathogenesis and use of fecal microbiota modification in the treatment should be studied extensively.Prevention of this silent epidemic by spreading awareness and early intervention should be our priority.

Sarcopenia and metabolic dysfunction associated steatotic liver disease:Time to address both

Sarcopenia and metabolic dysfunction associated steatotic liver disease(MASLD)are closely intertwined.Sarcopenia,traditionally a disease of the older adult and chronic disease population,has been closely studied as one of the pathophysiologic conditions at play in the development of MASLD.They share similar risk factors of insulin resistance and physical inactivity.Given similar pathophysiology along the liver-muscle axis,sarcopenia has been studied as a risk factor for MASLD,and vice versa.Current research suggests a bidirectional relationship.Given the chronicity of MASLD as a chronic inflammatory liver disease,it can break down muscle mass and lead to sarcopenia,while sarcopenia promotes intramuscular lipid accumulation that releases cytokines that can aggravate inflammation in the liver.However,for the longest time,a lack of consensus definition for MASLD and sarcopenia made it difficult to study their relationship and outcomes.A recent nomenclature update to diagnosing MASLD has made it easier for researchers to identify cohorts for study.However,no gold standard technique to measure muscle mass or consensus sarcopenia definition has been identified yet.Future studies are needed to reach a consensus and reduce diagnostic variation.With similar pathophysiology and shared risk factors between the two diseases,future research may also identify potential therapeutic targets along the liver-muscle axis that would benefit both sarcopenia and MASLD in order to maximize their outcomes.

Advances in sepsis-associated liver dysfunction

Recent studies have revealed liver dysfunction as an early event in sepsis. Sepsis-associated liver dysfunction is mainly resulted from systemic or microcirculatory disturbances, spillovers of bacteria and endotoxin (lipopolysaccharide, LPS), and subsequent activa-tion of inflammatory cytokines as well as mediators. Three main cell types of the liver which contribute to the hepatic response in sepsis are Kupffer cells (KCs), hepatocytes and liver sinusoidal endothelial cells (LSECs). In addition, activated neutrophils, which are also recruited to the liver and produce potentially destructive enzymes and oxygen-free radicals, may further enhance acute liver injury. The clinical manifestations of sepsis-associated liver dysfunction can roughly be divided into two categories: Hypoxic hepatitis and jaundice. The latter is much more frequent in the context of sepsis. Hepatic failure is traditionally considered as a late manifestation of sepsis-induced multiple organ dysfunction syndrome. To date, no specific therapeutics for sepsis-associated liver dysfunction are available. Treatment measure is mainly focused on eradication of the underlying infection and management for se-vere sepsis. A better understanding of the pathophysiology of liver response in sepsis may lead to further increase in survival rates.

Insulin resistance and adipose tissue interactions as the cornerstone of metabolic(dysfunction)-associated fatty liver disease pathogenesis

The relationship between metabolic derangements and fatty liver development are undeniable,since more than 75% of patients with type 2 diabetes mellitus present with fatty liver.There is also significant epidemiological association between insulin resistance(IR)and metabolic(dysfunction)-associated fatty liver disease(MAFLD).For little more than 2 years,the nomenclature of fatty liver of non-alcoholic origin has been intended to change to MAFLD by multiple groups.While a myriad of reasons for which MAFLD is thought to be of metabolic origin could be exposed,the bottom line relies on the role of IR as an initiator and perpetuator of this disease.There is a reciprocal role in MAFLD development and IR as well as serum glucose concentrations,where increased circulating glucose and insulin result in increased de novo lipogenesis by sterol regulatory elementbinding protein-1c induced lipogenic enzyme stimulation;therefore,increased endogenous production of triglycerides.The same effect is achieved through impaired suppression of adipose tissue(AT)lipolysis in insulin-resistant states,increasing fatty acid influx into the liver.The complementary reciprocal situation occurs when liver steatosis alters hepatokine secretion,modifying fatty acid metabolism as well as IR in a variety of tissues,including skeletal muscle,AT,and the liver.The aim of this review is to discuss the importance of IR and AT interactions in metabolic altered states as perhaps the most important factor in MAFLD pathogenesis.

Implications of metabolic dysfunction associated fatty liver disease in COVID-19

Metabolic associated fatty liver disorder(MAFLD)characterizes the contributing etiologies(i.e.,type 2 diabetes mellitus,metabolic syndrome,overweight)of individuals with fatty liver disease that affects 1/3rd of the world population.In 2020,the coronavirus disease 2019(COVID-19)crisis was unprecedented,and people with different comorbidities became more susceptible to the infection caused by severe acute respiratory syndrome coronavirus 2.MAFLD patients are frequently obese with added metabolic menace like diabetes,hypertension,and dyslipidemia leading to greater jeopardy of COVID-19.MAFLD patients are 4 to 6-fold more prone towards infections.COVID-19 induces liver injury with elevated levels of aspartate aminotransferase and alanine aminotransferase and insignificantly elevated bilirubin.Hence,MAFLD in COVID-19 patients worsens the condition significantly.The evidence highlighting the interaction between MAFLD and altered liver functioning in COVID-19 suggested that COVID-19 patients with pre-existing MAFLD are at greater risk of morbidity or intensive care unit admission.Direct hepatic injury,enhanced levels of inflammatory cytokines,declined hepatic mitochondrial activity,and compromised immunity are considered as some underlying mechanisms.The main focus of this review is to discuss the implications of metabolic dysfunction associated with fatty liver disease in COVID-19 patients.The review systematically analyzes the effect of striking two worldwide pandemics(MAFLD and COVID-19)together in the present era.

Fournier gangrene in an infant, complicated with severe sepsis and liver dysfunction: A case report

BACKGROUND Fournier gangrene is a rare,life-threatening infection characterized by necrotizing fasciitis in the perineal,genital and/or lower abdominal regions.Despite its rarity,the unfavorable prognosis associated with this disease is dependent on the timing of medical care.CASE SUMMARY A 3-month-old boy was admitted to our pediatric intensive care unit in critical condition after a 5-day history of fever and scrotal erythema with breaching skin lesions and swelling.Despite ambulatory antibiotic treatment,the child’s clinical condition deteriorated.At the time of admission,the child had necrotizing scrotal fasciitis that had spread to the abdomen.Following reanimation,the surgeon decided on an immediate intervention to rule out testicular torsion and to debride the affected area.Despite optimal antibiotic and supportive therapy,the patient developed severe sepsis with liver dysfunction,making treatment more challenging.CONCLUSION Recognizing Fournier gangrene,prompt referral to pediatric surgery,and appropriate antibiotic coverage are critical for avoiding sepsis and multiorgan dysfunction.

Liver dysfunction-related COVID-19:A narrative review

The coronavirus 2019 disease(COVID-19)is caused by a novel coronavirus,severe acute respiratory syndrome coronavirus 2.This disease was designated by the World Health Organization as a pandemic on March 11,2020,which is not seen before.There are no classical features among the cases of the disease owing to the involvement of nearly all body tissues by the virus.Hepatic involvement is one of the characteristics of the COVID-19 course.There are six possible mechanisms of such involvement:Direct virus injury,drug-induced effect,inflammatory cytokine storm,hypoxia-ischemic destruction,abnormalities in liver function tests,and pre-existing chronic liver diseases.Liver abnormalities are seen commonly in the severe or critical stage of COVID-19.Therefore,these abnormalities determine the COVID-19 severity and carry a high rate of morbidity and mortality.The elderly and patients with comorbidities like diabetes mellitus and hypertension are more vulnerable to liver involvement.Another issue that needs to be disclosed is the liver manifestations following the COVID-19 vaccination,such as autoimmune hepatitis.Of note,complete vaccination with third and fourth booster doses is necessary for patients with previous chronic liver diseases or those who have been subjected to liver transplantation.This review aims to explore the various aspects of liver dysfunction during the COVID-19 course regarding the epidemiological features,predisposing factors,pathophysiological mechanisms,hepatic manifestations due to COVID-19 or following vaccination,role of liver function tests in the assessment of COVID-19 severity,adverse effects of the therapeutic agents for the disease,and prognosis.

Non-alcoholic fatty liver disease and thyroid dysfunction:A systematic review

Thyroid hormones are totally involved in the regulation of body weight, lipid metabolism, and insulin resistance. Therefore it is anticipated that thyroid hormones may have a role in the pathogenesis of non alcoholic fatty liver disease(NAFLD) and non alcoholic steatohepatitis(NASH). In this study, we reviewed the current literature on the association between thyroid dysfunction and NAFLD/NASH. A search for English language medical literature reporting an association between thyroid dysfunction and NAFLD/NASH in humans was conducted across PubMed, ISI Web of Science, and Scopus in August, 2013. Out of 140 studies initially identified through the search, 11 relevant articles were included in the final review. Thyroid dysfunctions in the form of overt or subclinical hypothyroidism are prevalent among patients with NAFLD/NASH. Hypothyroidism appears to be an independent risk factor for NAFLD/NASH in some studies; however, other newly published studies failed to find such anassociation. The results of the studies on the role of thyroid abnormalities in NAFLD/NASH are inconsistent, and further research is recommended to determine the relationship between hypothyroidism and NAFLD/NASH and the underlying mechanisms.

Risk factors, surgical complications and graft survival in liver transplant recipients with early allograft dysfunction

Background: Early allograft dysfunction (EAD) is a severe complication after liver transplantation. The associated risk factors and complications have re-gained recent interest. This study investigated risk factors, survival and complications associated with EAD in a large liver transplant center in Latin America. Methods: Retrospective, unicenter, cohort, based on data from adult patients undergoing first deceaseddonor liver transplant from January 2009 to December 2013. EAD was defined by one or more of the following:(i) bilirubin ≥10 mg/dL on postoperative day 7;(ii) international normalized ratio ≥1.6 on postoperative day 7, and (iii) alanine aminotransferase or aspartate aminotransferase > 2000 IU/L within the first seven days after transplant. Results: A total of 602 patients were included;of these 34.2% developed EAD. Donor risk factors were male ( P = 0.007), age between 50 and 59 years ( P = 0.034), overweight ( P = 0.028) or grade I obesity ( P = 0.012), sodium > 157 mmol/L ( P = 0.002) and grade IV ischemia/reperfusion injury ( P = 0.002). Cold ischemia time ≥10 h ( P = 0.008) and warm ischemia time ≥40 min ( P = 0.013) were the surgical factors. Male ( P < 0.001) was the only recipient protective factor. Compared with the non-EAD group, patients with EAD were submitted to more reoperations (24.3% vs. 13.4%, P = 0.001) and had higher graft loss rates (37.9% vs. 21.2%, P < 0.001), with similar patient survival rates ( P = 0.238). Conclusions: EAD risk factors are related to donor, surgical procedure and recipient. Donor risk factors for EAD were male, age between 50 and 59 years, donor overweight or grade Ⅰ obesity, sodium > 157 mmol/L and grade Ⅳ ischemia/reperfusion injury. Cold ischemia time ≥10 h and warm ischemia time ≥40 min were the surgical risk factors. Male was the only recipient protective factor. Patients with EAD had higher reoperations and graft loss rates.

Effectiveness and Safety of Double-balloon Catheter versus Intra-amniotic Injection of Ethacridine Lactate for Termination of Second Trimester Pregnancy in Patients with Liver Dysfunction

Severe liver dysfunction in pregnancy（SLDP） is rare but serious complications with high mortality rate. This study compared the effectiveness and safety of double-balloon catheter versus intra-amniotic injection of ethacridine lactate for the termination of second trimester pregnancy in patients with SLD. A total of 55 patients with indications of labor induction were enrolled and analyzed by retrospective control analysis method. Twenty-three cases adopted Cook double balloon dilation as Cook group, and 32 cases received intra-amniotic injection of ethacridine lactate as EL group. The primary outcome was evaluated by successful abortion rate and the difference in the induction-to-abortion interval. Secondary outcomes included liver function recovery and the frequency of adverse events. Both Cook and EL regimens were effective, with successful abortion rate of 87.0% and 93.8%, respectively（P=0.639）. The induction-to-delivery interval was similar between Cook group and EL group（38.1±21.5 vs. 41.3±17.4, P=0.543）. The liver disease status was more severe in Cook group than in EL group, but it did not show any significant difference after pregnancy termination between the two groups and the improvement rate also did not show any significant difference. Both treatments were safe and there was no significant difference in bleeding and cervical laceration adverse events between the two groups. Our study firstly compared double-balloon catheter and ethacridine lactate for the induction of labor in women with SLD during second trimester pregnancy.

Evaluation of the updated definition of early allograft dysfunction in donation after brain death and donation after cardiac death liver allografts

BACKGROUND:An updated definition of early allograft dysfunction(EAD) was recently validated in a multicenter study of 300 deceased donor liver transplant recipients.This analysis did not differentiate between donation after brain death(DBD) and donation after cardiac death(DCD) allograft recipients.METHODS:We reviewed our prospectively entered database for all DBD(n=377) and DCD(n=38) liver transplantations between January 1,2006 and October 30,2011.The incidence of EAD as well as its ability to predict graft failure and survival was compared between DBD and DCD groups.RESULTS:EAD was a valid predictor of both graft and patient survival at six months in DBD allograft recipients,but in DCD allograft recipients there was no significant difference in the rate of graft failure in those with EAD(11.5%) compared with those without EAD(16.7%)(P=0.664) or in the rate of death in recipients with EAD(3.8%) compared with those without EAD(8.3%)(P=0.565).The graft failure rate in the first 6 months in those with international normalized ratio ≥1.6 on day 7 who received a DCD allograft was 37.5% compared with 6.7% for those with international normalized ratio <1.6 on day 7(P=0.022).CONCLUSIONS:The recently validated definition of EAD is a valid predictor of patient and graft survival in recipients of DBD allografts.On initial assessment,it does not appear to be a useful predictor of patient and graft survival in recipients of DCD allografts,however a study with a larger sample size of DCD allografts is needed to confirm these findings.The high ALT/AST levels in most recipients of DCD livers as well as the predisposition to biliary complications and early cholestasis make these parameters as poor predictors of graft failure.An alternative definition of EAD that gives greater weight to the INR on day 7 may be more relevant in this population.

Liver cirrhosis and left ventricle diastolic dysfunction: Systematic review

BACKGROUND Liver cirrhosis is a chronic hepatic disease which is associated with cardiovascular abnormalities.Hyperdynamic circulation in liver cirrhosis causes functional and structural cardiac alterations.The prevalence of left ventricle diastolic dysfunction(LVDD)in cirrhotic patients ranges from 25.7%to as high as 81.4%as reported in different studies.In several studies the severity of diastolic dysfunction(DD)correlated with a degree of liver failure and the rate of dysfunction was higher in patients with decompensated cirrhosis compared with compensated.Future directions of comprehensive assessment of cardiac function in cirrhotic patients might provide a better prognosis for these patients.AIM To clarify the correlation between the severity of liver cirrhosis and left ventricle diastolic dysfunction in the existing literature.METHODS Through January and February of 2019 at Vilnius University we conducted a systematic review of the global existing literature on the prevalence of left ventricle diastolic dysfunction in patients with liver cirrhosis.We searched for articles in PubMed,Medline and Web of science databases.Articles were selected by using adequate inclusion and exclusion criteria.Our interest was the outcome of likely correlation between the severity of cirrhosis[evaluated by Child-Pugh classes,Model For End-Stage Liver Disease(MELD)scores]and left ventricle diastolic dysfunction[classified according to American Society of Echocardiography(ASE)guidelines(2009,2016)],as well as relative risk of dysfunction in cirrhotic patients.Subgroup analyses were performed to evaluate the ratio and grades of left ventricle diastolic dysfunction with respect to cirrhosis severity.RESULTS A total of 1149 articles and abstracts met the initial search criteria.Sixteen articles which met the predefined eligibility criteria were included in the final analysis.Overall,1067 patients(out of them 723 men)with liver cirrhosis were evaluated for left ventricle diastolic dysfunction.In our systemic analysis we have found that 51.2%of cirrhotic patients had left ventricle diastolic dysfunction diagnosed and the grade 1 was the most prevalent(59.2%,P<0.001)among them,the grade 3 had been rarely diagnosed-only 5.1%.The data about the prevalence of diastolic dysfunction in cirrhotic patients depending on Child-Pugh Classes was available from 5 studies(365 patients overall)and only in 1 research diastolic dysfunction was found being associated with severity of liver cirrhosis(P<0.005).We established that diastolic dysfunction was diagnosed in 44.6%of Child-Pugh A class patients,in 62%of Child B class and in 63.3%of Child C patients(P=0.028).The proportion of patients with higher diastolic dysfunction grades increases in more severe cirrhosis presentation(P<0.001).There was no difference between mean MELD scores in patients with and without diastolic dysfunction and in different diastolic dysfunction groups.In all studies diastolic dysfunction was more frequent in patients with ascites.CONCLUSION This systemic analysis suggests that left ventricle diastolic dysfunction is an attribute of liver cirrhosis which has not received sufficient attention from clinicians so far.Future suggestions of a comprehensive assessment of cardiac function in cirrhotic patients might provide a better prognosis for these patients and give hint for better understanding of the left ventricle diastolic dysfunction pathogenesis in liver cirrhosis.

Primary graft dysfunction after liver transplantation

BACKGROUND: Primary graft dysfunction (PGD) causes complications in liver transplantation, which result in poor prognosis. Recipients who develop PGD usually experience a longer intensive care unit and hospital stay and have higher mortality and graft loss rates compared with those without graft dysfunction. However, because of the lack of universally accepted definition, early diagnosis of graft dysfunction is difficult. Additionally, numerous factors affect the allograft function after transplantation, making the prediction of PGD more difficult. The present review was to analyze the literature available on PGD and to propose a definition.DATA SOURCE: A search of PubMed (up to the end of 2012) for English-language articles relevant to PGD was performed to clarify the characteristics, risk factors, and possible treatments or interventions for PGD.RESULTS: There is no pathological diagnostic standard; many documented definitions of PGD are different. Many factors such as donor status, procurement and transplant process and recipient illness may affect the function of graft, and ischemia reperfusion injury is considered the direct cause. Potentia managements which are helpful to improve graft function were investigated. Some of them are promising.CONCLUSIONS: Our analyses suggested that the definition of PGD should include one or more of the following variables: (1)bilirubin ≥10 mg/dL on postoperative day 7; (2) internationa normalized ratio ≥1.6 on postoperative day 7; and (3) alanine aminotransferase or aspartate aminotransferase 】2000 IU/L within 7 postoperative days. Reducing risk factors may decrease the incidence of PGD. A majority of the recipients could recover from PGD; however, when the graft progresses intoprimary non-function, the patients need to be treated with retransplantation.

Hepatic flow is an intraoperative predictor of early allograft dysfunction in whole-graft deceased donor liver transplantation: An observational cohort study

BACKGROUND Early allograft dysfunction(EAD)after liver transplantation(LT)is an important cause of morbidity and mortality.To ensure adequate graft function,a critical hepatocellular mass is required in addition to an appropriate blood supply.We hypothesized that intraoperative measurement of portal venous and hepatic arterial flow may serve as a predictor in the diagnosis of EAD.AIM To study whether hepatic flow is an independent predictor of EAD following LT.METHODS This is an observational cohort study in a single institution.Hepatic arterial blood flow and portal venous blood flow were measured intraoperatively by transit flow.EAD was defined using the Olthoff criteria.Univariate and multivariate analyses were used to determine the intraoperative predictors of EAD.Survival analysis and prognostic factor analysis were performed using the Kaplan-Meier and Cox regression models.RESULTS A total of 195 liver transplant procedures were performed between January 2008 and December 2014 in 188 patients.A total of 54(27.7%)patients developed EAD.The median follow-up was 39 mo.Portal venous flow,hepatic arterial flow(HAF)and total hepatic arterial flow were associated with EAD in both the univariate and multivariate analyses.HAF is an independent prognostic factor for 30-d patient mortality.CONCLUSION Intraoperative measurement of blood flow after reperfusion appears to be a predictor of EAD;Moreover,HAF should be considered a predictor of 30-d patient mortality.

Early markers of reperfusion injury after liver transplantation: association with primary dysfunction

BACKGROUND： In patients with end-stage fiver disease, fiver transplantation is the only available curative treatment. Al- though the outcome and quality of life in the patients have improved over the past decades, primary dys- or nonfimction （PDF/PNF） can occur. Early detection of PDF and PNF is crucial and could lead to individual therapies. This study was designed to identify early markers of reperfusion injury and PDF in liver biopsies taken during the first hour after reperfusion.

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.

Zinc finger protein A20 protects rats against chronic liver allograft dysfunction

AIM:To investigate the effect of zinc finger protein A20 on chronic liver allograft dysfunction in rats.METHODS:Allogeneic liver transplantation from DA rats to Lewis rats was performed.Chronic liver allograft dysfunction was induced in the rats by administering low-dose tacrolimus at postoperative day (POD) 5.Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer administered intravenously every 10 d starting from POD 10.The recipient rats were injected with physiological saline,rAdEasy-A20 (1 × 109 pfu/30 g weight) or rAdEasy (1 × 109 pfu/30 g weight) every 10 d through the tail vein for 3 mo starting from POD 10.Liver tissue samples were harvested on POD 30 and POD 60.RESULTS:Liver-transplanted rats treated with only tacrolimus showed chronic allograft dysfunction with severe hepatic fibrosis.A20 overexpression ameliorated the effects on liver function,attenuated liver allograft fibrosis and prolonged the survival of the recipient rats.Treatment with A20 suppressed hepatic protein production of tumor growth factor (TGF)1,interleukin1 ,caspase-8,CD40,CD40L,intercellular adhesion molecule-1,vascular cell adhesion molecule-1 and E-selectin.A20 treatment suppressed liver cell apoptosis and inhibited nuclear factorB activation of Kupffer cells (KCs),liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs),and it subsequently decreased cytokine mRNA expression in KCs and LSECs and reduced the production of TGF1 in HSCs.CONCLUSION:A20 might prevent chronic liver allograft dysfunction by re-establishing functional homeostasis of KCs,LSECs and HSCs.