HALT-C试验中伴有重度肝纤维变性的丙型肝炎患者的认知功能

Background/Aims: Prior studies have demonstrated neuropsychological abnormalities in chronic hepatitis C (CHC) patients even with mild fibrosis. The aim of this study was to determine the frequency, type, and severity of cognitive impairment in a large group of CHC patients with advanced fibrosis. Methods: Ten validated neuropsychological tests were administered to 201 CHC patients. Standard scores for individual tests were calculated using normative population data that controlled for age, gender, and/or education. Lifetime psychiatric history, alcohol consumption, and mood status were also determined. Results: 33% of patients met criteria for cognitive impairment (i.e. standard score < 40 on at least 4 tests). Mild impairment in verbal recall and working memory were noted with other domains remaining intact. Liver disease severity and lifetime psychiatric/substance abuse history did not correlate with group mean cognitive test results or the presence of cognitive impairment. In contrast, IQ and depression scores were significant and independent predictors of cognitive impairment (ROC=0.84) . Conclusions: 33% of patients entering the HALT-C trial have evidence of a mild, non-focal subcortical processing deficit which was highly correlated with IQ, education, and occupation. Future studies of cognitive function in CHC patients should control for general cognitive ability.

铁超负荷与BMT后肝纤维变性的危险性

现有报道称,经骨髓移植(BMT)治疗的地中海贫血病人患进行性肝纤维变性的危险与铁超负荷和丙型肝炎病毒(HCV)感染相互关联。

中西医结合治疗肝豆状核变性肝纤维化的临床观察

目的 :观察中西医结合治疗肝豆状核变性肝纤维化的临床疗效。方法 :将 38例肝豆状核变性肝纤维化患儿随机分为治疗组和对照组。治疗组 2 6例 ,在采用西药护肝、降酶等治疗的基础上 ,加用软坚糖浆 ;对照组 12例 ,单用西药治疗。结果 :治疗组ALT复常率为 84 6 1% ,血清学肝纤维化指标均明显下降 ,与对照组比较有显著性差异 (P <0 0 5 )。结论 :中西医结合治疗肝豆状核变性肝纤维化有改善肝功能和抗肝纤维化的作用。

200例慢性肝病患者血清免疫学指标与肝纤维化指标的典型相关分析

目的：研究慢性肝病患者血清免疫学指标与肝纤维化指标的相关关系。方法：对２００例慢性肝病患者的８个血清免疫学指标和９个与肝纤维化有关的血清生化指标进行典型相关分析。结果：血清免疫学指标与肝纤维化指标的典型相关系数为０．８１３ ９（Ｐ＝０．０００１），在这两个因素集团相关中，血清免疫学指标中起主要作用的是免疫球蛋白ＩｇＧ、ＩｇＭ和ＩｇＡ，其次为白细胞介素－２和自然杀伤细胞；肝纤维化指标中起主要作用的是凝血酶原时间和α２巨球蛋白，其次为透明质酸和转铁蛋白。结论：机体的免疫功能和肝纤维化密切相关。

DMN纤维肝细胞的功能变化及扶正化瘀药物血清对其的影响

应用血清药理学方法研究DMN纤维肝细胞的功能变化及扶正化瘀方对其的影响。结果表明:纤维肝细胞增殖功能、AIb分泌功能较正常肝细胞低下,而胶原生成率及ALT、AST活性则显著升高;扶正化瘀方药物血清能明显抑制纤维肝细胞增殖及其胶原生成率,抑制培养液中ALT、AST活性,促进AIb分泌量,这可能是该方抗肝纤维化的作用机制之一,并在一定程度上发现了该方扶正(促进AIb合成)与化瘀(抑制胶原生成)的双重作用。

益气活血合剂抗牛血清白蛋白免疫性肝纤维化作用的实验研究

44只Wistar雌性大白鼠随机分为正常对照、病理对照、益气活血、养阴活血4组,于攻击注射4次后,益气活血和养阴活血组各以300%的益气活血和养阴活血合剂灌胃40天。结果益气活血合剂有改善肝组织病理、降低肝胶原蛋白含量、提高红细胞清除免疫复合物功能及调整体液免疫反应作用。

重组HGF可抑制大鼠肝硬变的发生和发展

大阪大学医学部教授中村敏一等小组用大鼠实验证明,通过使用基因重组人肝细胞生长因子(rHGF)能抑制纤维变性和肝硬变,促进没有纤维化的肝再生。在大阪召开的第67届日本生化学会上发表了此成果。对人也一样,HGF能抑制慢性肝病患者晚期病态-肝纤维变性和肝硬变的发生、发展,有可能成为防止肝硬性盱功能不全的治疗药。 该小组给肝硬变模型大鼠(在腹腔内使用了低浓度的二甲基亚硝胺(DMN)而制成的)在改变条件的同时静脉注射用CHO细胞分泌生产的rHGF,探讨其在生存率、组织学、血液生化学等方面有无差异。与开始使用DMN同时连续使用rHGF,可明显地抑制肝纤维变性的发生。另外。

脂肪肝与心脏有何关系

肝脏是体内最大的器官,身负数百种重要职能。举几个例子来说,它将食物转化成能源,加工胆固醇,清除血液中有害毒素,制造有助于血液凝结的蛋白质。但是,现在许多人肝脏内可能有危险性脂肪累积,令人担忧。非酒精性脂肪肝（简称NAFLD）是慢性肝脏疾病的主要病因。人们越来越认识到它是心脏疾病的原因之一。

德国丙型肝炎(基因1b型)单源性暴发结果:一项25年的多中心研究

Background/Aims: The natural course of the hepatitis C virus genotype 1b (HCV-1b) infection is still unclear but important for therapeutic decisions. There are few unbiased long-term follow-up studies with known dates of infection. Methods: Between August 1978 and March 1979, 14 HCV-1b contaminated batches of anti-D immunoglobulin had been administered to 2867 women for prophylaxis of rhesus isoimmunization throughout East Germany. We reexamined 1980 women, representing 70% of the total cohort of 15 centers. Results: After application of the contaminated anti-D, 93% of the recipients developed an acute hepatitis C. After 25 years, 86% of the 1833 affected women still tested positive for hepatitis C virus antibodies and 46% for HCV RNA. Only nine (0.5% ) had overt liver cirrhosis, 30 women (1.5% ) developed precirrhotic stages and one HCC was diagnosed. Ten (0.5% ) died of HCV related complications, half of these related to additional comorbidity. In the last 5 years, a continuous, but low increase of fibrotic scores was observed. Conclusions: Young women without comorbidity may clear HCV (1b) infection in more than half of the cases, or develop mild chronic hepatitis C. We confirmed the low risk of progression to cirrhosis in this cohort within 25 years.

Diabetes mellitus, insulin resistance and hepatitis C virus infection: A contemporary review

AIM To summarise the literature data on hepatitis C virus(HCV)-infected patients concerning the prevalence of glucose abnormalities and associated risk.METHODS We conducted a PubM ed search and selected all studies found with the key words "HCV" or "hepatitis C virus" and "diabetes" or "insulin resistance". We included only comparative studies written in English or in French, published from January 2000 to April 2015. We collected the literature data on HCV-infected patients concerning the prevalence of glucose abnormalities [diabetes mellitus (DM) and insulin resistance (IR)] and associated risk [i.e., severe liver fibrosis, response to antivirals, and the occurrence of hepatocellular carcinoma(HCC)]. RESULTS HCV infection is significantly associated with DM/IR compared with healthy volunteers and patients with hepatitis B virus infection. Glucose abnormalities were associated with advanced liver fibrosis, lack of sustained virologic response to interferon alfa-based treatment and with a higher risk of HCC development. As new antiviral therapies may offer a cure for HCV infection, such data should be taken into account, from a therapeutic and preventive point of view, for liver and non-liver consequences of HCV disease. The efficacy of antidiabetic treatment in improving the response toantiviral treatment and in decreasing the risk of HCC has been reported by some studies but not by others. Thus, the effects of glucose abnormalities correction in reducing liver events need further studies.CONCLUSION Glucose abnormalities are strongly associated with HCV infection and show a negative impact on the main liver related outcomes.

Ultrasound shear wave elastography and liver fibrosis: A Prospective Multicenter Study

AIM To assess the accuracy of shear wave elastography(SWE) alone and in combination with aminotransferase platelet ratio index(APRI) score in the staging of liver fibrosis.METHODS A multicenter prospective study was conducted to assess the accuracy of SWE(medians) and APRI to predict biopsy results. The analysis focused on distinguishing the different stages of liver disease, namely, F0 from F1-4, F0-1 from F2-4, F0-2 from F3-4 and F0-3 from F4; F0-F1 from F2-F4 being of primary interest. The area under the receiver operating characteristic(AUROC) curve was computed using logistic regression model. The role of age, gender and steatosis was also assessed.RESULTS SWE alone accurately distinguished F0-1 from F2-4 with a high probability. The AUROC using SWE alone was 0.91 compared to 0.78 for using the APRI score alone.The APRI score, when used in conjunction with SWE, did not make a significant contribution to the AUROC. SWE and steatosis were the only significant predictors that differentiated F0-1 from F2-4 with an AUROC of 0.944.CONCLUSION Our study validates the use of SWE in the diagnosis and staging of liver fibrosis. Furthermore, the probability of a correct diagnosis is significantly enhanced with the addition of steatosis as a prognostic factor.

Caffeic acid phenethyl ester up-regulates antioxidant levels in hepatic stellate cell line T6 via an Nrf2-mediated mitogen activated protein kinases pathway

AIM To investigate the antioxidant effect of caffeic acid phenethyl ester(CAPE) in hepatic stellate cell-T6(HSC-T6) cells cultured in vitro and the potential mechanisms.METHODS HSC-T6 cells were cultured in vitro and treated with various concentrations of CAPE for 24, 48 and 72 h, respectively. Cell proliferation was investigated using the MTT assay, and cell ultrastructural alterations were observed by transmission electron microscopy. Flow cytometry was employed to investigate the effects of CAPE on apoptosis and the levels of reactive oxygen species in HSC-T6 cells cultured in vitro. An enzyme immunoassay instrument was used to evaluate antioxidant enzyme expression. The effect on α-smooth muscle actin was shown using immunofluorescence. Gene and protein levels of Nrf2, related factors, and mitogen activated protein kinases(MAPKs), in HSC-T6 cells were detected using RT-PCR and Western blot, respectively.RESULTS CAPE inhibited the proliferation and activation of HSC-T6 cells cultured in vitro. CAPE increased the antioxidant levels and the translocation of Nrf2 from the cytoplasm to the nucleus in HSC-T6 cells. Moreover,the phosphorylation of MAPKs in cells decreased in response to CAPE. Interestingly, CAPE-induced oxidative stress in the cells was significantly attenuated by pretreatment with MAPKs inhibitors.CONCLUSION CAPE inhibits cell proliferation and up-regulates the antioxidant levels in HSC-T6 cells partly through the Nrf2-MAPKs signaling pathway.

Role of circulating microRNAs in liver diseases

MicroRNAs(miRNAs) are small RNAs regulate gene expression by inhibiting the turnover of their target mRNAs. In the last years, it became apparent that miRNAs are released into the circulation and circulating miRNAs emerged as a new class of biomarkers for various diseases. In this review we summarize available data on the role of circulating miRNAs in the context of acute and chronic liver diseases including hepatocellular and cholangiocellular carcinoma. Data from animal models are compared to human data and current challenges in the field of miRNAs research are discussed.

Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin,TGF-β1,IL-13 and oxidative stress

AIM To evaluate the therapeutic effects of bone marrowderived CD11b+CD14+ monocytes in a murine model of chronic liver damage. METHODS Chronic liver damage was induced in C57BL/6 mice by administration of carbon tetrachloride and ethanol for 6 mo. Bone marrow-derived monocytes isolated by immunomagnetic separation were used for therapy. The cell transplantation effects were evaluated by morphometry,biochemical assessment,immunohistochemistry and enzyme-linked immunosorbent assay. RESULTS CD11b+CD14+ monocyte therapy significantly reduced liver fibrosis and increased hepatic glutathione levels. Levels of pro-inflammatory cytokines,including tumor necrosis factor-α,interleukin(IL)-6 and IL-1β,in addition to pro-fibrotic factors,such as IL-13,transforming growth factor-β1 and tissue inhibitor of metalloproteinase-1 also decreased,while IL-10 and matrix metalloproteinase-9 increased in the monocytetreated group. CD11b+CD14+ monocyte transplantation caused significant changes in the hepatic expression of α-smooth muscle actin and osteopontin. CONCLUSION Monocyte therapy is capable of bringing about improvement of liver fibrosis by reducing oxidative stress and inflammation,as well as increasing antifibrogenic factors.

Influence of vitamin D on liver fibrosis in chronic hepatitis C: A systematic review and meta-analysis of the pooled clinical trials data

AIM To investigate the relationship between vitamin D and liver fibrosis in hepatitis C-monoinfected or hepatitis C virus(HCV)-human immunodeficiency virus(HIV) coinfected patients. METHODS Pertinent studies were located by a library literature search in PubM ed/Embase/Cochrane/Scopus/LILACS by two individual reviewers. Inclusion criteria:(1) studies with patients with HCV or co-infected HCV/HIV;(2) studies with patients ≥ 18 years old;(3) studies that evaluated liver fibrosis stage, only based on liver biopsy; and(4) studies that reported serum or plasma 25(OH)D levels. Studies that included pediatric patients, other etiologies of liver disease, or did not use liver biopsy for fibrosis evaluation, or studies with inadequate data were excluded. Estimated measures of association reported in the literature, as well as corresponding measures of uncertainty, were recorded and corresponding odds ratios with 95%CI were included in a meta-analysis. RESULTS The pooled data of this systematic review showed that 9 of the 12 studies correlated advanced liver disease defined as a Metavir value of F3/4 with 25(OH) D level insufficiency. The meta-analysis indicated a significant association across studies.CONCLUSION Low vitamin D status is common in chronic Hepatitis C patients and is associated with advanced liver fibrosis.

M2-like Kupffer cells in fibrotic liver may protect against acute insult

AIM To investigate the mechanism of hepatoprotection conferred by liver fibrosis through evaluating the activation phenotype of kupffer cells.METHODS Control and fibrotic mice were challenged with a lethal dose of D-Gal N/lipopolysaccharide(LPS),and hepatic damage was assessed by histology,serum alanine transferase(ALT)levels,and hepatic expression of HMGB1,a potent pro-inflammatory mediator.The localization of F4/80(a surrogate marker of KCs),HMGB1,and type I collagen(Col-1)was determined by immunofluorescence staining.The phenotype of KCs was characterized by real-time PCR.KCs isolated from control or fibrotic mice were challenged with LPS or HMGB1 peptide,and HMGB1 translocation was analyzed.RESULTS Liver fibrosis protected mice against D-Gal N/LPS challenge,as shown by improved hepatic histology and reduced elevation of ALT compared with the normal mice treated in the same way.This hepatoprotection was also accompanied by inhibition of HMGB1 expression in the liver.Co-localization of F4/80,HMGB1,and Col-1 was found in fibrotic livers,indicating the close relationship between KCs,HMGB1 and liver fibrosis.KCs isolated from fibrotic mice predominantly exhibited an M2-like phenotype.In vitro experiments showed that HMGB1 was localized in the nucleus of the majority of M2-like KCs and that the translocation of HMGB1 was inhibited following stimulation with LPS or HMGB1 peptide,while both LPS and HMGB1 peptide elicited translocation of intranuclear HMGB1 in KCs isolated from the control mice.CONCLUSION M2-like Kupffer cells in fibrotic liver may exert a protective effect against acute insult by inhibiting the translocation of HMGB1.

cytoplasmic domain of tissue factor promotes liver fibrosis in mice

AIM To evaluate the role of tissue factor(TF) and protease activated receptor(PAR)-2 in liver fibrosis.METHODS Using CCl4 administration for eight weeks, we induced hepatic fibrosis in wild-type C57BL/6 mice and in mice with deletion of the cytoplasmic signalling domain of TF(TF§CT/§CT), deletion of PAR-2(PAR-2-/-) and combined deletion of TF signalling domain and PAR-2(TF§CT/§CT/PAR-2-/-). Hepatic fibrosis area was assessed by quantitative imaging of picrosirius red staining. Hepatic collagen content was assessed by hydroxyproline levels. Hepatic stellate cells(αSMA positive) and hepatic macrophages(CD68 positive) were identified by immunohistochemistry. Hepatic gene expression was determined by PCR and liver TGFβ1 content by ELISA.RESULTS CCl4 treated mice with deletion of the PAR-2 gene(PAR-2-/-) and the cytoplasmic domain of TF(TF§CT/§CT) developed significantly less hepatic fibrosis, characterised by reduced liver fibrosis area and hydroxyproline content, compared to control wildtype mice treated with CCl4. The observed reduction in histological fibrosis was accompanied by a significant decrease in the hepatic content of TGFβ, the prototypic fibrogenic cytokine, as well as fewer activated hepatic stellate cells and hepatic macrophages. Deletion of the TF cytoplasmic signalling domain reduced hepatic fibrosis to levels similar to thoseobserved in mice lacking PAR-2 signalling but combined deletion provided no added protection against fibrosis indicating a lack of mutual modulating effects that have been observed in other contexts such as angiogenic responses.CONCLUSION Tissue factor cytoplasmic domain is involved in TF-PAR-2 signalling initiating hepatic fibrosis and is a potential therapeutic target, as its deletion would not impact coagulation.

Clinical impact of occult hepatitis B virus infection in immunosuppressed patients

Occult hepatitis B infection(OBI), is characterized by low level hepatitis B virus(HBV) DNA in circulating blood and/or liver tissue. In clinical practice the presence of antibody to hepatitis B core antigen in hepatitis B surface antigen(HBsAg)-/anti-HBs-negative subjects is considered indicative of OBI. OBI is mostly observed in the window period of acute HBV infection in blood donors and in recipients of blood and blood products, in hepatitis C virus chronic carriers, in patients under pharmacological immunosuppression, and in those with immunodepression due to HIV infection or cancer. Reactivation of OBI mostly occurs in anti-HIV-positive subjects, in patients treated with immunosuppressive therapy in onco-hematological settings, in patients who undergo hematopoietic stem cell transplantation, in those treated with anti-CD20 or anti-CD52 monoclonal antibody, or anti-tumor necrosis factors antibody for rheumatological diseases, or chemotherapy for solid tumors. Under these conditions the mortality rate for hepatic failure or progression of the underlying disease due to discontinuation of specific treatment can reach 20%. For patients with OBI, prophylaxis with nucleot(s)ide analogues should be based on the HBV serological markers, the underlying diseases and the type of immunosuppressive treatment. Lamivudine prophylaxis is indicated in hemopoietic stem cell transplantation and in onco-hematological diseases when high dose corticosteroids and rituximab are used; monitoring may be indicated when rituximab-sparing schedules are used, but early treatment should be applied as soon as HBsAg becomes detectable. This review article presents an up-to-date evaluation of the current knowledge on OBI.

Cost-effectiveness of enhanced liver fibrosis test to assess liver fibrosis in chronic hepatitis C virus and alcoholic liver disease patients

AIM To assess liver fibrosis(LF) in hepatitis C virus(HCV) and alcoholic liver disease(ALD), estimate health outcomes and costs of new noninvasive testing strategies METHODS A Markov model was developed to simulate LF progression in HCV and ALD for a cohort of 40-yearold men with abnormal levels of transaminases. Three different testing alternatives were studied: a single liver biopsy; annual Enhanced liver fibrosis(ELF?) followed by liver stiffness measurement(LSM) imaging as a confirmation test if the ELF test is positive; and annual ELF test without LSM. The analysis was performed from the perspective of a university hospital in Spain.Clinical data were obtained from published literature. Costs were sourced from administrative databases of the hospital. Deterministic and probabilistic sensitivity analyses were performed.RESULTS In HCV patients, annual sequential ELF test/LSM and annual ELF test alone prevented respectively 12.9 and 13.3 liver fibrosis-related deaths per 100 persons tested, compared to biopsy. The incremental costeffectiveness ratios(ICERs) were respectively €13400 and €11500 per quality-adjusted life year(QALY). In ALD, fibrosis-related deaths decreased by 11.7 and 22.1 per 100 persons tested respectively with sequential ELF test/LSM and annual ELF test alone. ICERs were €280 and €190 per QALY, respectively.CONCLUSION The use of the ELF test with or without a confirmation LSM are cost-effective options compared to a single liver biopsy for testing liver fibrosis in HCV and ALD patients in Spain.