Imaging of the chemotherapy-induced hepatic damage:Yellow liver,blue liver,and pseudocirrhosis

The liver is the major drug-metabolizing and drug-detoxifying organ.Many drugs can cause liver damage through various mechanisms;however,the liver response to injury includes a relatively narrow spectrum of alterations that,regardless of the cause,are represented by phlogosis,oxidative stress and necrosis.The combination of these alterations mainly results in three radiological findings:vascular alterations,structural changes and metabolic function reduction.Chemotherapy has changed in recent decades in terms of the drugs,protocols and duration,allowing patients a longer life expectancy.As a consequence,we are currently observing an increase in chemotherapy-associated liver injury patterns once considered unusual.Recognizing this form of damage in an early stage is crucial for reconsidering the therapy regimen and thus avoiding severe complications.In this frontier article,we analyze the role of imaging in detecting some of these pathological patterns,such as pseudocirrhosis,“yellow liver”due to chemotherapy-associated steatosis-steatohepatitis,and“blue liver”,including sinusoidal obstruction syndrome,veno-occlusive disease and peliosis.

Extrahepatic collaterals and liver damage in embolotherapy for ruptured hepatic artery pseudoaneurysm following hepatobiliary pancreatic surgery

AIM: To evaluate the effects of extrahepatic collaterals to the liver on liver damage and patient outcome after embolotherapy for the ruptured hepatic artery pseudoa- neurysm following hepatobiliary pancreatic surgery. METHODS: We reviewed 9 patients who underwent transcatheter arterial embolization (TAE) for the ruptured hepatic artery pseudoaneurysm following major hepato- biliary pancreatic surgery between June 1992 and April 2006. We paid special attention to the extrahepatic arte- rial collaterals to the liver which may affect post-TAE liver damage and patient outcome. RESULTS: The underlying diseases were all malignan- cies, and the surgical procedures included hepatopancre- atoduodenectomy in 2 patients, hepatic resection with removal of the bile duct in 5, and pancreaticoduodenec- tomy in 2. A total of 11 pseudoaneurysm developed: 4 in the common hepatic artery, 4 in the proper hepatic artery, and 3 in the right hepatic artery. Successful he- mostasis was accomplished with the initial TAE in all patients, except for 1. Extrahepatic arterial pathways to the liver, including the right inferior phrenic artery, the jejunal branches, and the aberrant left hepatic artery, were identified in 8 of the 9 patients after the completion of TAE. The development of collaterals depended on the extent of liver mobilization during the hepatic resection, the postoperative period, the presence or absence of an aberrant left hepatic artery, and the concomitant arte- rial stenosis adjacent to the pseudoaneurysm. The liver tolerated TAE without significant consequences when at least one of the collaterals from the inferior phrenic ar-tery or the aberrant left hepatic artery was present. One patient, however, with no extrahepatic collaterals died of liver failure due to total liver necrosis 9 d after TAE. CONCLUSION: When TAE is performed on ruptured hepatic artery pseudoaneurysm, reduced collateral path- ways to the liver created by the primary surgical proce- dure and a short postoperative interval may lead to an unfavorable outcome.

Protective effect of antioxidant on renal damage caused by Doxorubicin chemotherapy in mice with hepatic cancer

Objective:To investigate the protective effects and mechanism of antioxidant TBHQ on renal damage caused by doxorubicin chemotherapy in mice with hepatic cancer.Methods:Cell H22 of mice with hepatic cancer which was subcultured for three times was subcutaneously transplanted to the groin of right lower limb of 45 SPF Kunming mice to establish the transplanted tumor model.The doxorubicin chemotherapy group and antioxidant intervention group received intraperitoneal injection of ADM(1 mg/kg·0.2 mL/2d).The model control group received normal saline(NS) of the same volume at the same time.1%TBHQ was added into the diet of mice of the antioxidant intervention group.Seven weeks later,morning urines and peripheral blood were randomly collected to detect UAIb,UCr,BUN,Scr and UAlb/Cr levels.All mice were beheaded.The renal tissues were made into homogenate,and SOD,T-AOC and MDA content in tissues were detected followed by cell lysis.All data were processed using SPSS 19.0.Results:The UAlb/Cr,BUN.Scr and MDA of doxorubicin chemotherapy group were significantly higher those of model control group and the activities of SOD,T-AOC in doxorubicin chemotherapy group were lower than those of model control group(P<0.01).The UAlb/Cr,BUN,Scr and MDA of antioxidant intervention group were lower than those of doxorubicin chemotherapy group and the activities of SOD,T-AOC of antioxidant intervention group were higher than those of doxorubicin chemotherapy group doxorubicin chemotherapy group(P<0.05).The BUN of model control group was higher than that of blank group,and T-AOC was lower than that of blank group,and difference was statistically significant(P<0.05).Conclusions:Doxorubicin chemotherapy could lead to abnormal antioxidant capacity and renal function of tumor-bearing mice with hepatic cancer.TBHQ antioxidant intervention could effectively improve the antioxidant capacity of renal tissue and reduce the renal damage caused by doxorubicin to some extent.

Consequences of hepatic damage after traumatic brain injury: current outlook and potential therapeutic targets

Traumatic brain injury（TBI）triggers liver inflammation：TBI is a serious pathology affecting around 10 million people annually,being a persistent public health and medical problem Forceful impact while playing sports,falls,physical assault,or traffic accidents are common causes of head injury.

Chronic hepatitis C virus infection:Serum biomarkers inpredicting liver damage

Currently, a major clinical challenge in the management of the increasing number of hepatitis C virus(HCV) infected patients is determining the best means for evaluating liver impairment. Prognosis and treatment of chronic hepatitis C(CHC) are partly dependent on the assessment of histological activity, namely cell necrosis and inflammation, and the degree of liver fibrosis. These parameters can be provided by liver biopsy; however, in addition to the risks related to an invasive procedure, liver biopsy has been associated with sampling error mostly due to suboptimal biopsy size. To avoid these pitfalls, several markers have been proposed as non-invasive alternatives for the diagnosis of liver damage. Distinct approaches among the currently available non-invasive methods are(1) the physical ones based on imaging techniques; and(2) the biological ones based on serum biomarkers. In this review, we discuss these approaches with special focus on currently available non-invasive serum markers. We will discuss:(1) class?Ⅰ?serum biomarkers individually and as combined panels, particularly those that mirror the metabolism of liver extracellular matrix turnover and/or fibrogenic cell changes;(2) class Ⅱ biomarkers that are indirect serum markers and are based on the evaluation of common functional alterations in the liver; and(3) biomarkers of liver cell death, since hepatocyte apoptosis plays a significant role in the pathogenesis of HCV infection. We highlight in this review the evidence behind the use of these markers and assess the diagnostic accuracy as well as advantages, limitations, and application in clinical practice of each test for predicting liver damage in CHC.

Hepatitis C virus clearance and less liver damage in patients with high cholesterol, low-density lipoprotein cholesterol and APOE ε4 allele

BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modifying the course of the HCV infection.The relationship between cholesterol,APOE alleles,and the outcome of HCV infection has not been evaluated in the admixed population of Mexico.AIM To investigate the role of APOE-ε2,-ε3,and-ε4 alleles and the metabolic profile in the outcome of HCV infection.METHODS A total of 299 treatment-na?ve HCV patients were included in this retrospective study.Patients were stratified in chronic hepatitis C(CHC)(n=206)and spontaneous clearance(SC)(n=93).A clinical record was registered.Biochemical tests were assessed by dry chemistry assay.APOE genotypes were determined using a Real-Time polymerase chain reaction assay.RESULTS Total cholesterol,low-density lipoprotein cholesterol(LDL-c),triglycerides,and hypercholesterolemia were higher in SC than CHC patients as well as the frequency of the APOEε4 allele(12.4%vs 7.3%).SC patients were overweight(54.8%).Theε4 allele was associated with SC(OR=0.55,95%CI:0.31-0.98,P=0.042)and mild fibrosis(F1-F2)in CHC patients(OR 0.091,95%CI 0.01-0.75,P=0.020).LDL-c≥101.5 mg/dL(OR=0.20,95%CI:0.10-0.41,P<0.001)and BMI≥26.6 kg/m2(OR=0.37,95%CI:0.18-0.76,P<0.001)were associated with SC status;while ALT≥50.5 IU/L was negatively associated(OR=5.67,95%CI:2.69-11.97,P<0.001).CONCLUSION In SC patients,the APOEε4 allele and LDL-c conferred a protective effect in the course of the HCV infection in the context of excess body weight.

Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog

Hepatic ischemia-reperfusion syndrome has been the subject of intensive study and experimentation in recent decades since it is responsible for the outcome of several clinical entities,such as major hepatic resections and liver transplantation.In addition to the organ’s post reperfusion injury,this syndrome appears to play a central role in the dysfunction of distant tissues and systems.Thus,continuous research should be directed toward finding effective therapeutic options to improve the outcome and reduce the postoperative morbidity and mortality rates.Treprostinil is a synthetic analog of prostaglandin I2,and its experimental administration has shown encouraging results.It has already been approved by the Food and Drug Administration in the United States for pulmonary arterial hypertension and has been used in liver transplantation,where preliminary encouraging results showed its safety and feasibility by using continuous intravenous administration at a dose of 5 ng/kg/min.Treprostinil improves renal and hepatic function,diminishes hepatic oxidative stress and lipid peroxidation,reduces hepatictoll-like receptor 9 and inflammation,inhibits hepatic apoptosis and restores hepatic adenosine triphosphate(ATP)levels and ATP synthases,which is necessary for functional maintenance of mitochondria.Treprostinil exhibits vasodilatory properties and antiplatelet activity and regulates proinflam-matory cytokines;therefore,it can potentially minimize ischemia-reperfusion injury.Additionally,it may have beneficial effects on cardiovascular parameters,and much current research interest is concentrated on this compound.

Oxidative damage,pro-inflammatory cytokines,TGF-αand c-myc in chronic HCV-related hepatitis and cirrhosis

AIM: To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-αand c-myc. METHODS: The series included 37 patients with chronic active HCV-related hepatitis and 11 with HCV-related compensated cirrhosis. Eight-hydroxydeoxyguanosine in liver biopsies was quantified using an electrochemical detector. The mRNA expression of TIMF-α, IL-1β, TGF-αand c-myc in liver specimens was detected by semi-quantitative comparative RT-PCR. RESULTS: TNF-αlevels were significantly higher in hepatitis patients than in cirrhosis patients (P=0.05). IL-1βwas higher in cirrhosis patients (P=0.05). A significant correlation was found between TNF-αand staging (P=0.05) and between IL-1βlevels and grading (P=0.04). c-myc showed a significantly higher expression in cirrhosis patients (P=0.001). Eight-hydroxydeoxyguanosine levels were significantly higher in cirrhosis patients (P=0.05) and in HCV genotype 1 (P=0.03). Considering all patients, 8-hydroxydeoxyguanosine levels were found to be correlated with genotype (P=0.04) and grading (P=0.007). Also multiple logistic regression analysis demonstrated a significant correlation among the number of DNA adducts, TNF-αexpression and HCV genotype (P=0.02). CONCLUSION: In chronic HCV-related liver damage, oxidative DNA damage correlates with HCV genotype, grading and TNF-αlevels. As HCV-related liver damage progresses, TNF-αlevels drop while IL-1βand c-myc levels increase, which may be relevant to liver carcinogenesis.

Ataxia telangiectasia-mutated-Rad3-related DNA damage checkpoint signaling pathway triggered by hepatitis B virus infection

AIM: To explore whether acute cellular DNA damage response is induced upon hepatitis B virus (HBV) infection and the effects of the HBV infection.METHODS: We incubated HL7702 hepatocytes with HBV-positive serum,mimicking a natural HBV infection process.We used immunoblotting to evaluate protein expression levels in HBV-infected cells or in non-infected cells; immunofluorescence to show ATR foci ands Chk1 phosphorylation foci formation; flow cytometry to analyze the cell cycle and apoptosis; ultraviolet (UV) radiation and ionizing radiation (IR)-treated cells to mimic DNA damage; and Trypan blue staining to count the viable cells.RESULTS: We found that HBV infection induced an increased steady state of ATR protein and increased phosphorylation of multiple downstream targets including Chk1,p53 and H2AX.In contrast to ATR and its target,the phosphorylated form of ATM at Ser-1981 and its downstream substrate Chk2 phosphorylation at Thr-68 did not visibly increase upon infection.However,the level of Mre11 and p21 were reduced beginning at 0.5 h after HBV-positive serum addition.Also,HBV infection led to transient cell cycle arrest in the S and the G2 phases without accompanying increased apoptosis.Research on cell survival changes upon radiation following HBV infection showed that survival of UV-treated host cells was greatly increased by HBV infection,owing to the reduced apoptosis.Meanwhile,survival of IR-treated host cells was reduced by HBV infection.CONCLUSION: HBV infection activates ATR DNA damage response to replication stress and abrogates the checkpoint signaling controlled by DNA damage response.

Effect of an Airbag-selective Portal Vein Blood Arrester on the Liver after Hepatectomy:A New Technique for Selective Clamping of the Portal Vein

Objective:A novel technique was explored using an airbag-selective portal vein blood arrester that circumvents the need for an intraoperative assessment of anatomical variations in patients with complex intrahepatic space-occupying lesions.Methods:Rabbits undergoing hepatectomy were randomly assigned to 4 groups:intermittent portal triad clamping(PTC),intermittent portal vein clamping(PVC),intermittent portal vein blocker with an airbag-selective portal vein blood arrester(APC),and without portal blood occlusion(control).Hepatic ischemia and reperfusion injury were assessed by measuring the 7-day survival rate,blood loss,liver function,hepatic pathology,hepatic inflammatory cytokine infiltration,hepatic malondialdehyde levels,and proliferating cell nuclear antigen levels.Results:Liver damage was substantially reduced in the APC and PVC groups.The APC animals exhibited transaminase levels similar to or less oxidative stress damage and inflammatory hepatocellular injury compared to those exhibited by the PVC animals.Bleeding was significantly higher in the control group than in the other groups.The APC group had less bleeding than the PVC group because of the avoidance of portal vein skeletonization during hepatectomy.Thus,more operative time was saved in the APC group than in the PVC group.Moreover,the total 7-day survival rate in the APC group was higher than that in the PTC group.Conclusion:Airbag-selective portal vein blood arresters may help protect against hepatic ischemia and reperfusion injury in rabbits undergoing partial hepatectomy.This technique may also help prevent liver damage in patients requiring hepatectomy.

Non-steroidal anti-inflammatory drugs:What is the actual risk of liver damage?

Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a family of drugs, which taken as a group, represents one of the most frequently prescribed around the world. Thus, not surprisingly NSAIDs, along with antiinfectious agents, list on the top for causes of DrugInduced Liver Injury (DILI). The incidence of liver disease induced by NSAIDs reported in clinical studies is fairly uniform ranging from 0.29/100 000 [95% confidence interval (CI): 0.17-051] to 9/100 000 (95% CI: 6-15). However, compared with these results, a higher risk of liver-related hospitalizations was reported (3-23 per 100 000 patients). NSAIDs exhibit a broad spectrum of liver damage ranging from asymptomatic, transient, hyper-transaminasemia to fulminant hepatic failure. However, under-reporting of asymptomatic, mild cases, as well as of those with transient liver-tests alteration, in conjunction with reports non-compliant with pharmacovigilance criteria to ascertain DILI and flawed epidemiological studies, jeopardize the chance to ascertain the actual risk of NSAIDs hepatotoxicity. Several NSAIDs, namely bromfenac, ibufenac and benoxaprofen, have been withdrawn from the market due to hepatotoxicity; others like nimesulide were never marketed in some countries and withdrawn in others. Indeed, the contro-versy concerning the actual risk of severe liver disease persists within NSAIDs research. The present work intends (1) to provide a critical analysis of the dissimilar results currently available in the literature concerning the epidemiology of NSAIDS hepatotoxicity; and (2) to review the risk of hepatotoxicity for each one of the most commonly employed compounds of the NSAIDs family, based on past and recently published data.

Hepatic senescence, the good and the bad

Gradual alterations of cell’s physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells.Once becoming senescent,the cell stops dividing permanently but remains metabolically active.Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers,such as,morphological changes,expression of cell cycle inhibitors,senescence associatedβ-galactosidase activity,and changes in nuclear membrane.When cells in an organ become senescent,the entire organism can be affected.This may occur through the senescence-associated secretory phenotype(SASP).SASP may exert beneficial or harmful effects on the microenvironment of tissues.Research on senescence has become a very exciting field in cell biology since the link between age-related diseases,including cancer,and senescence has been established.The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence.The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes.Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration.This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.

Hepatitis C and pregnancy

Acute hepatitis C is a rare event in pregnancy. The most common scenario is chronic hepatitis C virus(HCV) infection in pregnancy. During pregnancy in women with chronic HCV infection a significant reduction in mean alanine aminotransferase levels has been reported,with a rebound during the postpartum period. In few cases exacerbation of chronic hepatitis C has been reported in pregnancy. A cofactor that might play a role in the reduction of liver damage is the release of endogenous interferon from the placenta. Observations regarding serum HCV-RNA concentration have been variable.In some women HCV-RNA levels rise toward the end of pregnancy. In general,pregnancy does not have a negative effect on HCV infection. Conversely,chronic hepatitis does not appear to have an adverse effect on the course of pregnancy,or the birth weight of the newborn infant. The role of spontaneous abortion is approximately the same as in the general population. The overall rate of mother-to-child transmission for HCV is3%-5% if the mother is known to be anti-HCV positive.Co-infection with human immunodeficiency virus(HIV)increases the rate of mother-to-child transmission up to19.4%. Numerous risk factors for vertical transmission have been studied. In general,high viral load defined as at least 2.5 × 106viral RNA copies/mL,HIV co-infection,and invasive procedures are the most important factors. Both interferon and ribavirin are contraindicated during pregnancy. Viral clearance prior to pregnancy increases the likelihood that a woman remains nonviremic in pregnancy with a consequent reduced risk of vertical transmission.

Hepatoprotective potential of petroleum ether leaf extract of Crossandra infundibuliformis on CCl_4 induced liver toxicity in albino mice

Objective:To analyze the hepatoprotective effect of the Crossandra infundibuliformis.Methods: Hepatotoxicity was induced by carbon tetrachloride.Petroleum ether extract of dried leaves was administrated to mice for 7 days.The hepatoprotective effect of petroleum ether extract was evaluated by the assay of liver function biochemical parameters.Results:The result clearly indicates that petroleum ether extract showed significant hepatoprotection when compared with standard Silumarin.Conclusions:The petroleum ether extract of the leaves of Crossandra infundibuliformis possess significant acute hepatoprotective activity.Thus further investigation on this species would bring a promising drug for liver disorders.

Cellular DNA repair cofactors affecting hepatitis B virus infection and replication

AIM: To investigate whether hepatitis B virus (HBV) infection activates DNA damage response and DNA repair cofactors inhibit HBV infection and replication. METHODS: Human hepatocyte cell line HL7702 was studied. Immunoblotting was performed to test the expression of ataxia telangiectasia-mutated (ATM)- Rad3-related protein (ATR), p21 and the level of phosphorylation of Chk1, p53, H2AX, ATM in HBV- infected or non-infected-cells. Special short RNAi oligos was transfected to induce transient ATR knockdown in HL7702. ATR-ATM chemical inhibitors caffeine (CF) and theophylline (TP), or Chk1 inhibitor 7-hydroxystaurosporine (UCN01) was studied to determine whether they suppress cellular DNA damage response and MG132 inhibits proteasome. RESULTS: The ATR checkpoint pathway, responding to single-strand breaks in DNA, was activated in response to HBV infection. ATR knockdown cells decreased the HBV DNA yields, implying that HBV infection and replication could activate and exploit the activated DNA damage response. CF/TP or UCN01 reduced the HBV DNA yield by 70% and 80%, respectively. HBV abrogated the ATR-dependent DNA damage signaling pathway by degrading p21, and introduction of the p21 protein before HBV infection reduced the HBV DNA yield. Consistent with this result, p21 accumulation after MG132 treatment also sharply decreased the HBVDNA yield. CONCLUSION: HBV infection can be treated with therapeutic approaches targeting host cell proteins by inhibiting a cellular gene required for HBV replication or by restoring a response abrogated by HBV, thus providing a potential approach to the prevention and treatment of HBV infection.

Investigation on correlation between expression of CD58 molecule and severity of hepatitis B

瞄准：调查在 CD58 的表示和肝炎 B 的严厉之间的关联。方法：在有肝炎 B 的病人的浆液的可溶的 CD58 (sCD58 ) 的水平被连接酶的免疫吸着剂试金检测。在 PBMC 的膜 CD58 分子的表示的水平被直接免疫荧光检测。血清 TBIL， DBIL， IBIL，中高音和著名计算机生产厂商的层次被自动化生物化学分析器也检测。结果：在浆液的 sCD58 和在有肝炎 B 的病人的 PBMC 的膜 CD58 分子的层次在正常控制比那显著地高(P 【 0.05 ) 。CD58 的水平与血清 TBIL， DBIL， IBIL，中高音和著名计算机生产厂商的层次有关。结论：CD58 分子的水平(在浆液和 PBMC 形式) 有肝炎的病人， B 与肝的度有关损坏。

Acute hepatitis associated with the use of natural product camu-camu

A 45-year-old previously healthy caucasian man was admitted for pruritus, scleral icterus and dark urine. The patient was reported to have taken a spoon of a preparation containing camu-camu (myrciaria dubia) a day. He took no other drugs and did not drink alcohol or use illicit substance. Laboratory studies reveiled an elevated aspartate transaminase of 403 U/L, and alanine transaminase of 1185 U/L, alkalinephosphatase of 335 U/L, gamma glutamyl transpeptidase of 300 U/L, and elevated total bilirubin of 142 μmol/L. His complete blood count was normal. Tests for viral, metabolic or autoimmune causes of liver injury were negative. Liver biopsy demonstrated centrilobular hepatocellular damage was compatible with drug toxicity which was not of very recent origin. Clinical and laboratory signs of liver injury gradually improved and the patient was discharged. Myrciaria dubia is used as a dietary supplement with antioxidant properties. To our knowledge, this is the first report of liver injury probably related to use of camu-camu. Exclusion of other causes and the histological diagnosis were compatible with drug toxicity render camu-camu which was most likely as the cause of acute heaptitis most likely. It is important to increase the awareness of both clinicians and patients about the potential dangers of herbal remedies in absence of reliable studies of clinical efficacy and benefit-risk assessment.

替诺福韦酯联合复方益肝灵片对肺结核合并HBV携带患者免疫功能及肝肾功能的影响

目的分析替诺福韦酯联合复方益肝灵片对肺结核合并乙型肝炎病毒(HBV)携带患者免疫功能及肝肾功能的影响。方法前瞻性选取2019年1月至2020年12月在秦皇岛市第二医院就诊的180例肺结核合并HBV感染患者作为研究对象,按照随机数字表法将其分为研究组和对照组,每组90例。对照组患者给予2HRZE/4HR常规化疗,同时采用葡醛内酯等进行常规保肝治疗,研究组患者在对照组治疗方案基础上加用口服富马酸替诺福韦二吡呋酯胶囊和复方益肝灵片。两组患者均连续治疗6个月,在治疗期间连续监测肝肾功能指标。对两组患者治疗6个月末时的病灶吸收和痰菌转阴比例进行比较;对两组患者治疗前和治疗6个月末时的HBV病毒载量、外周血CD4^(+)T淋巴细胞比例、CD8^(+)T淋巴细胞比例、CD4^(+)/CD8^(+)T淋巴细胞比值及血清肝功能指标[丙氨酸转移酶(ALT)、天冬氨酸转移酶(AST)、总胆红素]和肾功能指标(肌酐、尿素氮)水平进行比较;对两组患者治疗期间肝功能损害发生率及程度和肾功能损害发生率进行记录和比较。结果治疗6个月末,研究组患者病灶吸收、痰菌转阴的比例均高于对照组,差异均有统计学意义(P<0.05)。研究组患者的HBV载量较治疗前下降,对照组患者的HBV载量较治疗前上升,研究组患者治疗6个月末的HBV载量低于对照组,差异均有统计学意义(P<0.05)。研究组患者的外周血CD4^(+)T淋巴细胞比例和CD4^(+)/CD8^(+)T淋巴细胞比值均较治疗前升高,CD8^(+)T淋巴细胞比例较治疗前下降,差异均有统计学意义(P<0.05),而对照组患者外周血T淋巴细胞亚群指标与治疗前比较,差异均无统计学意义(P>0.05),研究组患者治疗6个月末的外周血CD4^(+)T淋巴细胞比例和CD4^(+)/CD8^(+)T淋巴细胞比值均高于对照组,CD8^(+)T淋巴细胞比例低于对照组,差异均有统计学意义(P<0.05)。两组患者的肝功能指标和肾功能指标均较治疗前升高,研究组患者治疗6个月末的ALT、AST、总胆红素、肌酐、尿素氮均低于对照组,差异均有统计学意义(P<0.05)。在治疗期间,研究组患者的肝功能损害和肾功能损害的发生率均低于对照组,肝功能损害程度分布低于对照组,差异均有统计学意义(P<0.05)。结论在肺结核合并HBV感染患者的治疗中,在常规抗结核化疗和保肝治疗基础上采用替诺福韦酯联合复方益肝灵片进行辅助治疗,能够显著提升化疗效果、有效降低HBV载量、调节免疫平衡、保护肝肾功能、减少化疗导致的药物性器官损害。

人参皂苷Rg1通过TLR4/MyD88/NF-κB p65通路调控小鼠急性肾损伤诱导的急性肝损伤的机制研究

目的:探讨人参皂苷Rg1(GRg1)对小鼠急性肾损伤所诱导的急性肝损伤的保护作用及其调控机制。方法:昆明小鼠随机分为假手术(sham)组、模型(model)组、GRg1组和necrostatin-1 (Nec-1)组,每组10只。制备急性肾损伤模型,24 h后收集血液。采用生化试剂盒检测小鼠血清肌酐(SCr)、血尿素氮(BUN)、天冬氨酸转氨酶(AST)、谷氨酸转氨酶(ALT)、丙二醛(MDA)和超氧化物歧化酶(SOD)水平。采用ELISA法检测炎症因子白细胞介素1β(IL-1β)、IL-6、IL-8和肿瘤坏死因子α(TNF-α)的表达。HE染色观察组织病理学改变,采用免疫组织化学和Western blot法检测TLR4、MyD88和NF-κB p65蛋白的表达水平。结果:与假手术组比较,model组小鼠出现明显的肝细胞坏死、肝肾功能减退,血清中SCr、BUN、AST和ALT均显著升高(P<0.01),MDA含量显著上升,SOD活性显著降低(P<0.01),且血清中炎症因子IL-1β、IL-6、IL-8和TNF-α含量显著升高(P<0.01),TLR4、MyD88和NF-κB p65蛋白表达显著增高(P<0.01);与model组相比,GRg1和Nec-1组处理后小鼠肝细胞坏死减轻,肝肾功能显著改善(P<0.01),血清中SCr、BUN、AST和ALT水平显著降低(P<0.01),MDA含量显著降低,SOD活性显著增高(P<0.01),血清中炎症因子IL-1β、IL-6、IL-8和TNF-α含量显著降低(P<0.01),TLR4、MyD88和NF-κB p65蛋白表达显著降低(P<0.01);GRg1组和Nec-1组小鼠上述指标比较差异无统计学意义。结论:GRg1可以改善小鼠急性肾损伤所致急性肝损伤的肝肾功能,其机制可能与抑制TLR4/MyD88/NF-κB p65信号通路有关。

人巨细胞病毒UL133基因型导致儿童肝功能损伤的机制研究

目的:探索人巨细胞病毒(HCMV)UL133基因型导致儿童肝功能损伤的分子机制。方法:(1)动物实验:将30只健康SD幼鼠依据随机数字表法分为空白组、对照组及实验组3组,每组10只。空白组幼鼠经尾静脉注射生理盐水,对照组幼鼠经尾静脉注射空载的腺病毒,实验组幼鼠经尾静脉注射携带UL133基因的慢病毒;使用小动物活体成像系统(NightOwlⅡLB 983活体光学分子影像系统)对每组幼鼠进行成像,确认其形成肝损伤模型。采用RT-PCR法检测3组幼鼠肝脏组织UL133RNA的表达量,ELISA法检测肝脏组织Caspase-3、Caspase-6及Toll样受体4(TLR4)受体的表达量,HE染色观察肝细胞变化,TUNEL法检测肝细胞的凋亡。(2)临床验证:选择人巨细胞病毒感染合并肝功能异常患儿为肝损害组(66例),无肝功能异常患儿为无肝损害组(64例)。通过原位杂交和PCR扩增检测患儿尿液HCMV基因型UL133和血清caspase-3、caspase-6的表达水平。结果:实验组幼鼠肝脏的荧光信号强度、肝细胞凋亡指数、UL133RNA、Caspase-3、Caspase-6及TLR4受体的表达水平均高于对照组和空白组(P<0.05),对照组和空白组比较差异无统计学意义(P>0.05)。肝损害组患儿尿液UL133阳性率、血液Caspase-3及Caspase-6的表达水平均高于无肝损害组(P<0.05)。结论:人巨细胞病毒UL133基因型可以诱导TLR4,致使效应分子Caspase-3和Caspase-6的表达增高,最终使得幼鼠肝脏受到损伤。感染UL133基因型巨细胞病毒的婴幼儿可因Caspase-3和Caspase-6的表达增加最终诱发肝脏损伤。