Ex vivo-expanded bone marrow stem cells home to the liver and ameliorate functional recovery in a mouse model of acute hepatic injury

BACKGROUND:Stem cell transplantation provides a theoretical approach for liver regeneration medicine;it may promote liver regeneration and self-repair.However,the transplantation of bone marrow-mesenchymal stem cells expanded ex vivo as a therapy for liver disease has rarely been investigated.This study aimed to explore whether bone marrow stem cells expanded ex vivo home to the liver and foster hepatic recovery after CCl 4 injury.METHODS:Bone marrow cells from BALB/c mice were expanded ex vivo by multiple-passage cultivation,characterized by cytoflow immunofluorescence,and pre-labeled with PKH26 before intravenous infusion into animals treated with CCl 4.The integration of bone marrow cells into the liver was examined microscopically,and plasma hepatic enzymes were determined biochemically.RESULTS:Cultured bone marrow cells exhibited antigenic profiles comparable to those of primary medullary stem cells.Double immunofluorescence showed colocalization of these cells with proliferative activity and albumin expression in the liver of CCl 4 -treated mice.Densitometry showed increased in situ cell proliferation (50±14 vs 20±3 cells/high-power field,P<0.05) and albumin expression (149±25 vs 20±5 cells/high-power field,P<0.05) in the liver,as well as reduced serum aminotransferase levels (P<0.05) and better survival rates (P<0.05) in animals receiving cultured bone marrow cells relative to controls.CONCLUSIONS:Ex vivo-expanded bone marrow cells are capable of relocating to and proliferating in the chemically- injured liver.Transplantation of these pluripotent stem cells appears to improve serum indices of liver function and survival rate in mice after CCl4-induced hepatic damage.

Early activated hepatic stellate cell-derived molecules reverse acute hepatic injury

AIM: To test whether hepatic stellate cells(HSCs) at different activation stages play different roles in acetaminophen(APAP)-induced acute liver injury(ALI).METHODS: HSCs were isolated from mouse liver and cultured in vitro.Morphological changes of initiation HSCs [HSCs(5d)] and perpetuation HSCs [HSCs(p3)] were observed by immunofluorescence and transmission electron microscopy.The protective effects of HSCderived molecules, cell lysates and HSC-conditioned medium(HSC-CM) were tested in vivo by survival and histopathological analyses.Liver injury was determined by measuring aminotransferase levels in the serum and by histologic examination of tissue sections under a light microscope.Additionally, to determine the molecular mediators of the observed protective effects of initiation HSCs, we examined HSC-CM using a highdensity protein array.RESULTS: HSCs(5d) and HSCs(p3) had different morphological and phenotypic traits.HSCs(5d) presented a star-shaped appearance with expressing α-SMA at non-uniform levels between cells.However, HSCs(p3) evolved into myofibroblast-like cells without lipid droplets and expressed a uniform and higher level of α-SMA.HSC-CM(5d), but not HSC-CM(p3), provided a significant survival benefit and showed a dramatic reduction of hepatocellular necrosis and panlobular leukocyte infiltrates in mice exposed to APAP.However, this protective effect was abrogated at higher cell masses, indicating a therapeutic window of effectiveness.Furthermore, the protein array screenrevealed that HSC-CM(5d) was composed of many chemokines and growth factors that correlated with inflammatory inhibition and therapeutic activity.When compared with HSC-CM(p3), higher levels of monocyte chemoattractant protein-1, macrophage inflammatory protein-1γ, hepatocyte growth factor, interleukin-10, and matrix metalloproteinase-2, but lower levels of stem cell factor and Fas-Ligand were observed in HSCCM(5d).CONCLUSION: These data indicated that initiation HSCs and perpetuation HSCs were different in morphology and protein expression, and provided the first experimental evidence of the potential medical value of initiation HSC-derived molecules in the treatment of ALI.

Effect of naked eukaryotic expression plasmid encoding rat augmenter of liver regeneration on acute hepatic injury and hepatic failure in rats

AIM: To study the protective effect of eukaryotic expression plasmid encoding augmenter of liver regeneration (ALR) on acute hepatic injury and hepatic failure in rats. METHODS: The PCR-amplified ALR gene was recombined with pcDNA3 plasmid, and used to treat rats with acute hepatic injury. The rats with acute hepatic injury induced by intraperitoneal injection of 2 mL/kg 50% carbon tetrachloride (CCl4) were randomly divided into saline control group and recombinant pcDNA3-ALR plasmid treatment groups. Recombinant pcDNA3-ALR plasmid DNA (50 or 200 μg/kg) was injected into the rats with acute hepatic injury intravenously, intraperitoneally, or intravenously and intraperitoneally in combination 4 h after CCl4 administration, respectively. The recombinant plasmid was injected once per 12 h into all treatment groups four times, and the rats were decapitated 12 h after the last injection. Hepatic histopathological alterations were observed after HE staining, the expression of proliferating cell nuclear antigen (PCNA) in liver tissue was detected by immunohistochemical staining, and the level of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was determined by biochemical method. The recombinant plasmid DNA (200 μg/kg) and saline were intraperitoneally injected into the rats with acute hepatic failure induced by intraperitoneal injection of 4 mL/kg 50% CCl4 after 4 h of CCl4 administration, respectively. Rats living over 96 h were considered as survivals.RESULTS: The sequence of ALR cDNA of recombinant pcDNA3-ALR plasmid was accordant with the reported sequence of rat ALR cDNA. After the rats with acute hepatic injury were treated with recombinant pcDNA3-ALR plasmid, the degree of liver histopathological injury markedly decreased. The pathologic liver tissues, in which hepatic degeneration and necrosis of a small amount of hepatocytes and a large amount of infiltrating inflammatory cells were observed, and they became basically normal in the most effective group after four times of injection of recombinant pcDNA3-ALR plasmid. The indexes of PCNA significantly increased in the recombinant pcDNA3-ALR plasmid treatment groups compared to model group. The level of serum AST and ALT remarkably reduced in recombinant pcDNA3-ALR plasmid treatment groups compared to model group. The results showed that the effect of 200 μg/kg recombinant pcDNA3-ALR plasmid in the rats with acute liver injury was stronger than that of 50μg/kg pcDNA3-ALR DNA.The effect of intravenous injection of recombinant pcDNA3ALR plasmid was better. After the rats with acute hepatic failure were treated with recombinant pcDNA3-ALR plasmid,the survival rate (40%) significantly increased in treatment groups compared to control group (15%, P＜0.01).CONCLUSION: The ALR gene may play an important role in relieving acute hepatic injury and hepatic failure by promoting hepatic cell proliferation and reducing level ofAST and ALT in CCl4-intoxicated rats.

Study progress on mechanism of severe acute pancreatitis complicated with hepatic injury

Study on the action mechanism of inflammatory mediators generated by the severe acute pancreatitis(SAP) in mul-tiple organ injury is a hotspot in the surgical field.In clinical practice,the main complicated organ dysfunctions are shock,res-piratory failure,renal failure,encephalopathy,with the rate of hepatic diseases being closely next to them.The hepatic injury caused by SAP cannot only aggravate the state of pancreatitis,but also develop into hepatic failure and cause patient death.Its complicated pathogenic mechanism is an obstacle in clinical treatment.Among many pathogenic factors,the changes of vasoac-tive substances,participation of inflammatory mediators as well as OFR(oxygen free radical),endotoxin,etc.may play important roles in its progression.

Study on protecting effects of Baicalin and Octreotide on hepatic injury in rats with severe acute pancreatitis

AIM: To investigate the protective effects and mechanisms of Baicalin and Octreotide on hepatic injury in rats with severe acute pancreatitis (SAP). METHODS: The SAP rat models were prepared and randomly assigned to the model control group, Baicalin treated group, and Octreotide treated group while other healthy rats were assigned to the sham-operated group. Rat mortality, levels of ALT, AST, liver and pancreas pathological changes in all groups were observed at 3, 6 and 12 h after operation. Tissue microarray (TMA) sections of hepatic tissue were prepared to observe expression levels of Bax, Bcl-2 protein and Caspase-3, and changes of apoptotic indexes.RESULTS: Rat survival at 12 h, expression levels of Bax, Caspase-3 protein and apoptotic indexes of liver were all significantly higher in treated groups than in model control group. While the liver and pancreas pathological scores, contents of ALT, AST, and expression levels of Bcl-2 protein were all lower in treated groups than in the model control group. CONCLUSION: Both Baicalin and Octreotide can protect rats with SAP by decreasing the contents of ALT, AST and expression levels of Bcl-2 protein, and improving the expression levels of Bax protein, Caspase-3 protein, and inducing apoptosis.

Effects of a combination of Japanese Raisin Tree Seed and Flower of Lobed Kudzuvine against acute alcohol-induced liver injury in mice

Objective:The Flower of Lobed Kudzuvine[Pueraria lobata(Willd.)Ohwi;Gehua in Chinese;GH]and Japanese Raisin Tree Seed(Hovenia dulcis Thunnb.;Zhijuzi in Chinese;ZJZ)are herbs that have been used in China for the treatment of alcohol intoxication and liver diseases.We aimed to evaluate the hepatoprotective potential of a combination of these in mice with acute alcohol-induced liver injury,and to elucidate the mechanisms involved.Methods:Male ICR mice were randomly allocated to six groups:a control group,an alcohol-administered group,and groups that were administered alcohol and one of silibinin,the GH,the ZJZ or a GH-ZJZ combination(at a ratio of 2:1).Animals were orally administered 56%alcohol(Er Guo-tou white spirit,0.12 mL/10 g/d)for 10 days and at the end of this period,hepatic biochemical indicators,antioxidant parameters,alcohol metabolic enzymes,and histopathologic changes were evaluated.Moreover,the expression of the signaling molecules KEAP1,NRF2,and AQP9 were measured by qRT-PCR and western blotting.Results:Compared with the model group,GH-ZJZ(2:1)had lower serum ALT(12.15±0.39,P紏.003),AST(104.07±1.03,P紏.001),and ALP(148.09±2.55,P紏.010)activities,and lower TC(1.97±0.05,P紏.001)and TG(1.54±0.07,P?.002)concentrations.GH-ZJZ(2:1)also significantly increased the hepatic activities of SOD and GSH(4.24±0.25 and 1.57±0.06,respectively;both P<.01),reduced the ROS and MDA concentrations(97.50±3.00 and 2.39±0.19,respectively;both P<.01),and upregulated Nrf2 expression(P<.01).GH-ZJZ(2:1)significantly reduced the expression of KEAP1 and AQP9 in the liver,compared with alcohol-administered mice(P<.01).Importantly,the GH-ZJZ combination caused a more marked improvement in acute liver injury than GH or ZJZ alone.Conclusion:We have demonstrated protective effects of GH-ZJZ(2:1)against acute alcohol-induced hepatic injury,and shown that these effects may be associated with improvements in lipid and alcohol metabolism,antioxidant capacity,and lipid peroxidation.

Research status of the mechanism and treatment for acute pancreatitis complicated with hepatic injury

Acute pancreatitis（AP） is characterized by its sudden onset and rapid progression and is often complicated by liver injury. APinduced liver injury may develop into hepatic failure and even result in death. Thus, it is of importance to protect liver function and block injury-related pathways. In the pathogenesis of liver injury in AP, inflammatory cytokines, nuclear factor-kappa B（NF- κB） and oxygen free radicals play important roles. The complexity of the mechanism underlying the development of liver injury exerts, to some extent, a contribution to the difficulties in the treatment of this disease. Currently, the drugs used to treat the disease include L-arginine （L-Arg）, calcium ion antagonists, somatostatin and a variety of inflammatory mediator inhibitors. Additionally, some traditional Chinese medicines such as tfipterygium, wilfordii, rhubarb and salvia milfiorrhizae may also have some effects. In this article, the pathogenesis of liver injury in AP and its therapy are reviewed.

Acute hepatitis of unknown etiology in an adult female:A case report

BACKGROUND Acute liver injury(ALI)refers to inflammation of the hepatic parenchyma without hepatic encephalopathy that lasts less than 6 mo.When the etiology is unknown,Acute Hepatitis of Unknown Origin(AHUO)can present as a diagnostic and treatment challenge.AHUO in the adult population is unusual and poorly documented.It has an incidence between 11%and 75%.Currently,no treatment guidelines exist.With no identified cause,treatment is often blind,and the wrong treatment plan may have unintended consequences.CASE SUMMARY We present the case of a 58-year-old woman who presented to the emergency room for elevated liver function tests(LFTs).Her symptoms started 10 d prior to admission and included nausea,vomiting,jaundice,decreased appetite,weight loss of 10 lbs,and dark urine.She denied drinking alcohol or taking any hepatotoxic agents,including acetaminophen,statins,vitamins,or supplements.She was admitted to the hospital,and an etiologic work-up was carried out.Her initial bloodwork revealed elevated liver enzymes(alanine aminotransferase 2500 U/L,aspartate aminotransferase 3159 U/L,and alkaline phosphatase 714 U/L)and elevated total bilirubin of 6.4 mg/dL.She tested negative for common infectious etiologies such as hepatotropic viruses A,B,C,and E.Further infective work-up revealed negative serology for cytomegalovirus,Epstein-Barr virus,herpes simplex virus 1&2,and human immunodeficiency virus.Her autoanti-body test results were negative,including anti-smooth muscle antibody,anti-mitochondrial antibody,and anti-liver kidney microsome 1 antibody.Magnetic resonance cholangiopancreatography ruled out biliary causes of elevated LFTs,and her core liver biopsy proved inconclusive.Over the course of her hospital stay,the patient's LFTs improved with supportive care and without steroids.CONCLUSION Idiopathic hepatitis makes treatment challenging.It can leave patients feeling confused and unfulfilled.Thus,educating the patient thoroughly for shared decision-making and management becomes essential.

Prognostic and diagnostic scoring models in acute alcoholassociated hepatitis:A review comparing the performance of different scoring systems

Alcohol-associated hepatitis(AAH)is a severe form of liver disease caused by alcohol consumption.In the absence of confounding factors,clinical features and laboratory markers are sufficient to diagnose AAH,rule out alternative causes of liver injury and assess disease severity.Due to the elevated mortality of AAH,assessing the prognosis is a radical step in management.The Maddrey discriminant function(MDF)is the first established clinical prognostic score for AAH and was commonly used in the earliest AAH clinical trials.A MDF>32 indicates a poor prognosis and a potential benefit of initiating corticosteroids.The model for end stage liver disease(MELD)score has been studied for AAH prognostication and new evidence suggests MELD may predict mortality more accurately than MDF.The Lille score is usually combined to MDF or MELD score after corticosteroid initiation and offers the advantage of assessing response to treatment a 4-7 d into the course.Other commonly used scores include the Glasgow Alcoholic Hepatitis Score and the Age Bilirubin international normalized ratio Creatinine model.Clinical AAH correlate adequately with histologic severity scores and leave little indication for liver biopsy in assessing AAH prognosis.AAH presenting as acute on chronic liver failure(ACLF)is so far prognosticated with ACLF-specific scoring systems.New artificial intelligence-generated prognostic models have emerged and are being studied for use in AAH.Acute kidney injury(AKI)is one possible complication of AAH and is significantly associated with increased AAH mortality.Predicting AKI and alcohol relapse are important steps in the management of AAH.The aim of this review is to discuss the performance and limitations of different scoring models for AAH mortality,emphasize the most useful tools in prognostication and review predictors of recurrence.

Hepatitis E virus in patients with acute severe liver injury

AIM: To examine the incidence of hepatitis E(HepE) in individuals with acute liver injury severe enough to warrant treatment at a transplant unit.METHODS: Hepatitis E virus(HEV) is an emerging pathogen in developed countries causing severe illness, particularly in immunocompromised patients or those with underlying chronic liver disease. HepE infection isoften under diagnosed, as clinicians can be reluctant to test patients who have not travelled to regions traditionally considered hyperendemic for HepE. There are few data regarding the significance of HEV in patients with very severe acute liver injury in developed countries. Eighty patients with acute severe liver injury attending the Scottish Liver Transplant unit were tested for HEV and anti-HEV IgG and IgM. Severe acute liver injury was defined as a sudden deterioration in liver function confirmed by abnormal liver function tests and coagulopathy or presence of hepatic encephalopathy. Eighty percent of these patients were diagnosed with paracetomol overdose. No patients had a history of chronic or decompensated chronic liver disease at time of sampling. IgG positive samples were quantified against the World Health Organization anti-HEV IgG standard. Samples were screened for HEV viral RNA by quantitative reverse transcription polymerase chain reaction.RESULTS: Four cases of hepatitis E were identified. Three of the four cases were only diagnosed on retrospective testing and were initially erroneously ascribed to drug-induced liver injury and decompensated chronic liver disease, with the cause of the decompensation uncertain. One case was caused by HEV genotype 1 in a traveller returning from Asia, the other three were autochthonous and diagnosed on retrospective testing. In two of these cases(where RNA was detected) HEV was found to be genotype 3, the most prevalent genotype in developed countries. Three patients survived, two of whom had been misdiagnosed as having drug induced liver injury. The fourth patient died from sepsis and liver failure precipitated as a result of hepatitis E infection and previously undiagnosed cirrhosis. Histopathology data to date is limited to mainly that seen for endemic HepE. All patients, with the exception of patient 1, demonstrated characteristics of HepE infection, as seen in previously described locally acquired cases.CONCLUSION: In patients with acute severe liver injury, HEV testing should be part of the initial diagnostic investigation algorithm irrespective of suspected initial diagnosis, age or travel history.

Sustained viral response of a case of acute hepatitis C virus infection via needle-stick injury

有感染由针棍子损害引起了的一个丙肝病毒(HCV ) 的一个 29 岁的护士与在尖锐肝炎的发作以后开始大约一年的干扰素贝它被对待。有一般疲劳，黄疸，和腹水的症状的耐心的发达尖锐丙肝在针棍子损害以后的 4 wk。当这些症状被介绍时，病人由人工授精是怀孕的。她希望了继续她的怀孕。在交货以后，生物化学的肝酶回到了正常层次。不过， HCV RNA 是积极的，病理学的发现显示了前进到慢性。遗传型是有低病毒的负担的 1b。在 600 万个单位的剂量的干扰素贝它的每日的静脉注射被开始并且继续八个星期。没有严重不利效果， HCV 被根除。在尖锐丙肝，推迟治疗被认为减少功效，但是干扰素贝它治疗是为在长期的阶段的丙肝感染的有用治疗之一。

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

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

Curcumin protects against acetaminophen-induced apoptosis in hepatic injury

AIM:To explore the effects of curcumin(CMN)on hepatic injury induced by acetaminophen(APAP)in vivo.METHODS:Male mice were randomly divided into three groups:groupⅠ(control)mice received the equivalent volumes of phosphate-buffered saline(PBS)intraperitoneally(ip);GroupⅡ[APAP+carboxymethylcellulose(CMC)]mice received 1%CMC(vehicle)2h before APAP injection;GroupⅢ(APAP+CMN)mice received curcumin(10 or 20 mg/kg,ip)2 h before before or after APAP challenge.In GroupsⅡandⅢ,APAP was dissolved in pyrogen-free PBS and injected at a single dose of 300 mg/kg.CMN was dissolved in 1%CMC.Mice were sacrificed 16 h after the APAP injection to determine alanine aminotransferase(ALT)levels in serum and malondialdehyde(MDA)accumulation,superoxide dismutase(SOD)activity and hepatocyte apoptosis in liver tissues.RESULTS:Both pre-and post-treatment with curcumin resulted in a significant decrease in serum ALT compared with APAP treatment group(10 mg/kg:801.46±661.34 U/L;20 mg/kg:99.68±86.48 U/L vs 5406.80±1785.75 U/L,P<0.001,respectively).The incidence of liver necrosis was significantly lowered in CMN treated animals.MDA contents were significantly reduced in 20 mg/kg CMN pretreatment group,but increased in APAP treated group(10.96±0.87 nmol/mg protein vs 16.03±2.58 nmol/mg protein,P<0.05).The decrease of SOD activity in APAP treatment group and the increase of SOD in 20 mg/kg CMN pretreatment group were also detected(24.54±4.95 U/mg protein vs 50.21±1.93 U/mg protein,P<0.05).Furthermore,CMN treatment efficiently protected against APAPinduced apoptosis via increasing Bcl-2/Bax ratio.CONCLUSION:CMN has significant therapeutic potential in both APAP-induced hepatotoxicity and other types of liver diseases.

Early acute kidney injury after liver transplantation: Predisposing factors and clinical implications

AIM To investigate the additional clinical impact of hepatic ischaemia reperfusion injury(HIRI) on patients sustaining acute kidney injury(AKI) following liver transplantation.METHODS This was a single-centre retrospective study of consecutive adult patients undergoing orthotopic liver transplantation(OLT) between January 2013 and June 2014. Early AKI was identified by measuring serum creatinine at 24 h post OLT(> 1.5 × baseline) or by the use of continuous veno-venous haemofiltration(CVVHF) during the early post-operative period. Patients with and without AKI were compared to identify risk factors associated with this complication. Peak serum aspartate aminotransferase(AST) within 24 h post-OLT was used as a surrogate marker for HIRI and severity was classified as minor(< 1000 IU/L), moderate(1000-5000 IU/L) or severe(> 5000 IU/L). The impact on time to extubation, intensive care length of stay, incidence of chronic renal failure and 90-d mortality were examined firstly for each of the two complications(AKI and HIRI) alone and then as a combined outcome. RESULTS Out of the 116 patients included in the study, 50% developed AKI, 24% required CVVHF and 70% sustainedmoderate or severe HIRI. Median peak AST levels were 1248 IU/L and 2059 IU/L in the No AKI and AKI groups respectively(P = 0.0003). Furthermore, peak serum AST was the only consistent predictor of AKI on multivariate analysis P = 0.02. AKI and HIRI were individually associated with a longer time to extubation, increased length of intensive care unit stay and reduced survival. However, the patients who sustained both AKI and moderate or severe HIRI had a longer median time to extubation(P < 0.001) and intensive care length of stay(P = 0.001) than those with either complication alone. Ninety-day survival in the group sustaining both AKI and moderate or severe HIRI was 89%, compared to 100% in the groups with either or neither complication(P = 0.049). CONCLUSION HIRI has an important role in the development of AKI post-OLT and has a negative impact on patient outcomes, especially when occurring alongside AKI.

Predictors of Mortality at 28-days in Infection associated Acute Kidney Injury in Cirrhosis

BACKGROUND Acute kidney injury(AKI)in cirrhosis is important complication with poor outcomes.And infections are common cause for acute decompensation.Infections in cirrhosis lead to acute deterioration of hemodynamics leading to precipitation of AKI.AIM To study predictors of mortality in patients with infection-associated AKI in cirrhosis.METHODS This was a prospective,observational study conducted at Tertiary care centre from January 2018 till April 2019.Total 119 participants with cirrhosis of liver presenting with AKI were included into the study.AKI was defined as per international club of Ascites-AKI criteria 2015.Patients were grouped into infection AKI and non-infection AKI.Non-infection AKI included patients with diuretic induced AKI and pre-renal AKI.Logistic regression analysis was used to determine predictors of mortality at 28-d.RESULTS Out of 119 patients,alcohol(n=104)was most common etiology of cirrhosis.The infection AKI included 67(56%)patients and non-infection AKI(n=52)included pre-renal AKI in 36(30%)and diuretic-induced AKI in 16(14%)patients.Infection AKI had significantly higher bilirubin,higher international normalized ratio(INR),low serum sodium,higher total leukocyte count(TLC)and higher prevalence of hepatic encephalopathy(HE)as compared to non-infection AKI.Infection AKI had higher progression of AKI(19/67 vs 2/52;P=0.01)and 28-d mortality(38/67 vs 4/5;P≤0.01)as compared to non-infection AKI.At 28-d,non-survivors(n=42)had significantly higher bilirubin,higher INR,low serum sodium,higher TLC and higher prevalence of HE as compared to survivors(n=77).On subgroup analysis of Infection AKI group,on multivariate analysis,serum bilirubin as well as presence of HE were independent predictors of 28-d mortality.There was no significant difference of mortality at 90-d between two groups.CONCLUSION Infection AKI in cirrhosis has a dismal prognosis with higher 28-d mortality as compared to noninfection AKI.Serum bilirubin and presence of HE predict 28-d mortality in infection AKI.

The Pathogenesis of Acute on Chronic Hepatitis B liver Failure

Acute-on-chronic liver failure is a characteristic clinical liver syndrome, which should be differentiated from acute liver failure, acute decompensated liver cirrhosis and chronic liver failure. The pathogenesis of ACLF is not fully understood yet. Viral factors and immune injury have been reported to be the two major pathogenesis. This paper reviewed the researches on the pathogenesis of acute on chronic hepatitis B liver failure in recent years, to provide theoretical basis for prompt and accurate diagnosis and treatment of this syndrome. This would benefit for the prognosis and raise the survival rate of patients.

Characteristics and Outcome of Exertional Heatstroke Patients Complicated by Acute Hepatic Injury:A Cohort Study

Background and Aims:Exertional heatstroke(EHS)is associated with strenuous physical activity in hot environments.The present study aimed to investigate dynamic changes of hepatic function indices in EHS patients and determine risk factors for death.Methods:This single-center retrospective cohort study considered all patients with EHS admitted to the intensive care unit at the General Hospital of Southern Theater Command of PLA from October 2008 to May 2019.Data on general characteristics,organ function parameters,and the 90-day outcome of enrolled patients were collected.Hepatic indices were collected dynamically,and patients with acute hepatic injury(AHI)were identified by plasma total bilirubin(TBIL)≥34.2μmol/L and an international normalized ratio≥1.5,or with any grade of hepatic encephalopathy.Results:In patients who survived,TBIL,alanine aminotransferase and aspartate aminotransferase were increased at 24 h,peaked at 2–3 days,and began to decrease at 5 days.In non-survivors,TBIL continuously increased post-admission.The area under the receiver operating characteristic curve for the prediction of mortality based on sequential organ failure assessment(SOFA)scores was 89.8%,and the optimal cutoff value was 7.5.Myocardial injury and infection were identified as independent risk factors for death in EHS patients with AHI.Conclusions:In EHS patients,hepatic dysfunction usually occurred within 24 h.Patients with AHI had more severe clinical conditions,and significantly increased 90-day mortality rates.SOFA scores over 7.5,complicated with myocardial injury or infection,were found to be risk factors for death in EHS patients with AHI.

乙型肝炎肝硬化发生急性肾损伤的影响因素及列线图预测模型构建

目的:探究乙型肝炎肝硬化发生急性肾损伤(AKI)的影响因素,构建列线图预测模型。方法:收集397例乙型肝炎肝硬化患者的临床资料,根据是否发生AKI将患者分AKI组(n=82)和非AKI组(n=315),比较两组患者的临床资料差异,采用多因素Logistic回归分析肝硬化AKI的影响因素。基于多因素分析结果构建列线图预测模型并验证,绘制预测模型校准曲线和ROC曲线下面积(AUC)。结果:研究共纳入397例乙型肝炎肝硬化患者,82例发生AKI,发生率约为20.7%。与非AKI组比较,AKI组患者在患病年龄≥50岁、失代偿期、腹水、上消化道出血、使用利尿剂和高Child-Pugh分级的发生率高,TBil、PT和PCT水平较高,而Alb和血清Na水平较低,差异具有统计学意义(均P<0.05)。多因素分析显示,Alb和血清Na为乙型肝炎肝硬化AKI的保护因素(OR=0.850和0.581,均P<0.05),而失代偿期、腹水、TBil升高、PT延长、PCT升高和Child-Pugh B/C级为危险因素(OR=3.398、7.013、1.146、1.314、1.969和26.230,均P<0.05)。列线图模型预测肝硬化AKI的AUC为0.901,校准曲线显示预测值与实测值基本相符。结论:失代偿期、腹水、TBil、PT和PCT水平升高、Alb和血清Na水平降低、Child-Pugh B/C级为乙型肝炎肝硬化发生AKI的独立危险因素。研究建立的列线图预测模型对乙型肝炎肝硬化AKI具有较好的预测准确度。

基于PPARγ/LXR-α信号通路探讨槲皮素对急性肺损伤肺泡巨噬细胞胞葬功能影响机制

目的 观察槲皮素对急性肺损伤大鼠肺泡巨噬细胞胞葬功能的影响,并基于过氧化物酶增殖物激活受体γ(PPARγ)/肝X受体α(LXR-α)信号通路研究其作用机制。方法 将60只雄性SD大鼠随机分为6组,每组10只。槲皮素低、中、高剂量组分别于造模前给予10 mg/kg、50 mg/kg、100 mg/kg的槲皮素灌胃,地塞米松组给予5 mg/kg的地塞米松灌胃,正常组和脂多糖组给予等量生理盐水灌胃,均1次/d。连续灌胃14 d后,除正常组外,其余组均采用鼻滴法给予脂多糖建立急性肺损伤模型。于造模后24 h,检测各组大鼠肺泡巨噬细胞胞葬功能,原位末端转移酶标记法(TUNEL)测定肺组织细胞凋亡率,ELISA法检测血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)水平,HE染色观察肺组织病理形态,免疫组化法检测肺组织中PPARγ、LXR-α、CD68蛋白阳性表达情况,RT-PCR法检测肺组织中PPARγ、LXR-α、CD68 mRNA表达情况。结果 与正常组比较,脂多糖组大鼠肺泡巨噬细胞胞葬功能明显减弱(P<0.05),肺组织细胞凋亡率和血清TNF-α、IL-1β、IL-6水平均明显增高(P均<0.05),血清IL-10水平明显降低(P<0.05),肺细胞肿胀、变性及大量炎性细胞浸润,肺组织中PPARγ、LXR-α、CD68蛋白阳性表达平均光密度值及mRNA相对表达量均明显降低(P均<0.05);与脂多糖组比较,槲皮素各组及地塞米松组大鼠肺泡巨噬细胞胞葬功能均明显增强(P均<0.05),槲皮素中、高剂量组及地塞米松组肺组织细胞凋亡率和血清TNF-α、IL-1β、IL-6水平均明显降低(P均<0.05),槲皮素各剂量组血清IL-10水平均明显升高(P均<0.05),槲皮素高剂量组肺组织病理损伤明显改善,槲皮素中、高剂量组PPARγ、LXR-α、CD68阳性表达平均光密度值和PPARγ、LXR-α、CD68 mRNA相对表达量均明显高于脂多糖组(P均<0.05),地塞米松组PPARγ和CD68阳性表达平均光密度值、PPARγ和LXR-α mRNA相对表达量均明显高于脂多糖组(P均<0.05)。结论 槲皮素可增强脂多糖诱导急性肺损伤大鼠肺泡巨噬细胞胞葬功能,减轻肺组织病理损伤,其机制可能与激活PPARγ/LXR-α信号通路有关。

护肝醒酒软糖混合液对小鼠急性酒精性肝损伤的保护作用

探究护肝醒酒软糖混合液(LSSCM)对小鼠急性酒精性肝损伤的保护作用。建立急性酒精性肝损伤模型,计算肝脏指数,测定血清中甘油三酯(TG)、丙氨酸氨基转移酶(ALT)、谷草转氨酶(AST)和肝组织中超氧化物歧化酶(SOD)、丙二醛(MDA)、乙醇脱氢酶(ADH)、乙醛脱氢酶(ALDH)的水平变化及通过肝组织病理切片分析其形态变化。结果表明,与模型组相比,LSSCM高剂量组肝脏指数、TG含量、MDA含量显著降低12.33%、48.35%、39.10%;SOD、ALDH、ADH水平显著提高18.61%、44.59%、124.61%;AST、ALT水平显著降低32.26%、40.71%;小鼠肝组织病理切片结果显示,LSSCM各剂量组小鼠受损肝脏均得到不同程度改善。综上所述,LSSCM对酒精所致的急性肝损伤小鼠的肝脏肿大、脂质代谢紊乱、肝脏氧化应激具有显著改善效果,可有效预防和改善急性酒精性肝损伤。