目的:探讨慢加急性肝衰竭(ACLF)患者发生肺部感染的危险因素及其对预后的影响,并建立预后预测模型.方法:回顾性分析310例ACLF患者的临床资料,通过Logistic回归分析ACLF患者发生肺部感染的危险因素,并利用Nomogram方法建立预后预测模型.结果:ACLF患者感染发生率65.5％,其中肺部感染发生率为38.7％.ACLF合并肺部感染患者较无感染及肺外感染患者的短期病死率更高.Logistic回归多因素分析显示肺部感染的独立危险因素包括侵入性操作、使用激素治疗及高敏C反应蛋白;而年龄、总胆红素、国际标准化比率(INR)以及合适的抗生素治疗是影响肺部感染患者30d病死率的独立危险因素.纳入相应的危险因素,建立名为TAIST的Nomo-gram预测模型,其受试者工作特征曲线下面积为0.844(95％CI0.741～0.946),具有比其他预后模型更高的判别性能.结论:ACLF合并肺部感染患者预后差,TAIST模型有助于早期识别其危险因素并优化治疗策略.

Aim: We aimed at investigating the effects of age on the predictive performances of noninvasive fibrosis scores for significant fibrosis in patients with chronic hepatitis B (CHB). Methods: A total of 496 CHB patients who underwent liver biopsy were stratified into four age groups: 30, 31 to 40, 41 to 50, and >= 51 years. Receiver operating characteristic curves were used to evaluate the diagnostic performance of aspartate aminotransferase to platelet ratio index (APRI), fibrosis score-4 (Fib-4) and.-glutamyl transpeptidase to platelet ratio (GPR) in different age groups. Results: The extent of fibrosis significantly increased with age, and the percentage of significant fibrosis (>= F2) was 21.3%, 29.0%, 38.5%, and 46.1%, respectively. All three scores displayed a moderate accuracy to diagnose significant fibrosis in overall patients. However, for patients with age <= 30 years, APRI, Fib-4, and GPR performed poorly with the AUROC of 0.567, 0.627 and 0.596, respectively. Furthermore, using the established cut-off values-1.45 for Fib-4, the sensitivity for significant fibrosis increased with age, from 14.8%, 38.1%, 74.5% to 97.87% in above age groups, respectively. To improve the diagnostic accuracy for significant fibrosis, the proposed low and high cut-off points for Fib-4were 0.41 and 1.15 in < 30 years, 0.8 and 1.59 in 31 to 40 years, 1.17 and 1.94 in 41 to 50 years, 1.76 and 3.10 in >= 51 years, respectively. Conclusions: Age may influence the diagnostic thresholds and performance of APRI, Fib-4, and GPR for significant fibrosis in patients with CHB. In particular, these scores performed poorly for identifying significant fibrosis in younger patients (<= 30 years).

BACKGROUND Chronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG). AIM To investigate the immune status of natural killer (NK) and T cells in different phases of chronic hepatitis B. METHODS The frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus (HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects. RESULTS The ability of NK cells to produce IFN-γ was markedly attenuated in HBV-infected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-α production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEG phases, as evidenced by the upregulation of NKp44 in CD56bright NK cells and CD69 in CD56dim NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-γ and TNF-α expression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases. CONCLUSION Our findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.

肝硬化失代偿期患者由于免疫功能低下,易继发真菌和(或)细菌感染.真菌多为条件致病菌,常见引起侵袭性肺部真菌感染的以曲霉菌属和白色假丝酵母菌最常见,其次为隐球菌、毛霉菌属[1].细菌则以大肠埃希菌为主,其次为肺炎克雷伯菌,当免疫功能异常,防御机制被破坏后,这些正常肠道寄生菌可转变为致病性强且耐药的菌种.一旦出现真菌、细菌的合并感染,病死率则明显提高,早期预防及明确致病菌,对于治疗具有重要意义.现就华中科技大学同济医学院附属同济医院收治的1例IgG4相关性自身免疫性肝炎(AIH)进展为失代偿期后并发侵袭性真菌重叠耐药细菌混合感染的病例报道如下.

This chapter describes the general treatment and immune principles and internal management for AECHB and HBV ACLF, including ICU monitoring, general supportive medications/nutrition/nursing, immune therapy, artificial liver supportive systems, hepatocyte/stem cell, and liver transplant, management for special populations, frequently clinical complications and the utilization of Chinese traditional medicines.

血小板减少是慢性肝病常见的并发症.不同原因导致的肝硬化均可伴发血小板减少症.在我国引起肝硬化的各种原因中,尤以慢性病毒性乙型及丙型肝炎、慢性血吸虫病、酒精性及非酒精性脂肪性肝病、自身免疫性肝病多见.慢性肝病并发血小板减少症与肝病严重程度及预后相关,并导致患者临床常规检查及治疗变得比较棘手.正确处理好血小板减少症对改善肝病患者的预后具有重要意义.

Objective We aim to characterize the complete cDNA sequence and the function of Tupaia belangeri ISG15, to offer molecular biology information for the study of HCV in Tupaia be-langeri.Material and Methods Primers were designed according to the consensus sequence of mammalian ISG15, and the complete cDNA sequence was cloned by Smarter RACE meth-od.Specific primers including restricted enzyme site were designed for complete cDNA amplifica-tion.PCR product was extracted and purified , and then cloned into the pMD 18-Tvector.Positive clones were selected by restricted enzyme digestion and sequenced .Homology analysis and phyloge-netic tree were calculated by software , and the secondary and 3-D structures of tupaia ISG15 were predicted by SWISS MODEL software .Results The complete sequence of 687 nucleotides and 157 amino acids of tupaia ISG 15 were obtained.The nucleotide and amino acid sequence of tupaia ISG 15 and human ISG15 shared a homology of 72.99%and 71.34%separately.Phylogenetic tree indica-ted that tupaia ISG15 was most related to primate species .SWISS MODEL prediction showed that tu-paia ISG15 had two ubiquitin-like domains, and the 3-D structure was similar to human ISG15, Er-rat and verify3 D evaluation results indicated that the predicated 3-D structure of tupaia ISG15 was stable and reliable.Conclusion Our results improved the understanding of tupaia as an animal model, offered important molecular biology information for the further in vivo study of innate immu-nity of HCV infection in Tupaia belangeri .

Background & Aims The natural course of chronic hepatitis B virus (HBV) infection is characterized by different immune responses, ranging from immune tolerant (IT) to immune activated (IA) stages. In our study, we investigated the natural killer (NK) cells activity in patients at different immunological stages of chronic HBV infection. Methods Blood samples obtained from 57 HBeAg positive patients with chronic hepatitis B (CHB), including 15 patients in the immune tolerant (IT) stage, 42 patients in the immune activated (IA) stage, and 18 healthy individuals (HI). The analyses included flow cytometry to detect NK cells, the determination of cytokine levels as well as of surface receptor expression and cytotoxicity. Results NK cells in peripheral blood were significantly lower in patients in the IA stage of CHB compared to HI (p<0.05). Patients in the IA stage of CHB had lower levels of NK cells activating receptor NKp30 and NKG2D expression, cytokine interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production, as compared to patients in the IT stage and HI, respectively (p<0.05). Cytotoxicity of NK cells was lower in patients in the IA stage of CHB compared to patients in the IT stage and HI, respectively (p<0.05). The level of IFN-γ but not level of TNF-α and cytotoxicity of NK cells was inversely correlated with serum HBV load in patients with CHB. Peripheral NK cells activity did not correlate with ALT level. Conclusion NK cells activity was lower in CHB patients, especially in those in the IA stage.

As a highly efficient delivery system, lentiviral vectors (LVs) have become a powerful tool to assess the antiviral efficacy of RNA drugs such as short hairpin RNA (shRNA) and decoys. Furthermore, recent advanced systems allow controlled expression of the effector RNA via coexpression of a tetracycline/doxycycline (DOX) responsive repressor (tTR-KRAB). Herein, this system was utilized to assess the antiviral effects of LV-encoded shRNAs targeting three conserved regions on the pregenomic RNA of hepatitis B virus (HBV), namely the region coding for the reverse transcriptase (RT) domain of the viral polymerase (LV-HBV-shRNA1), the core promoter (CP; LV-HBV-shRNA2), and the direct repeat 1 (DR1; LV-HBV-shRNA3). Transduction of just the LV-HBV-shRNA vectors into the stably HBV expressing HepG2.2.15 cell line showed significant reductions in secreted HBsAg and HBeAg, intracellular HBcAg as well as HBV RNA and DNA replicative intermediates for all vectors, however, most pronouncedly for the DR1-targeting shRNA3. The corresponding vector was therefore applied in the DOX-controlled system. Notably, strong interference with HBV replication was found in the presence of the inducer DOX whereas the antiviral effect was essentially ablated in its absence; hence, the silencing effect of the shRNA and consequently HBV replication could be strictly regulated by DOX. This newly established system may therefore provide a valuable platform to study the antiviral efficacy of RNA drugs against HBV in a regulated manner, and even be applicable in vivo.

This study aimed to evaluate the efficacy and safety of entecavir, lamivudine and telbivudine for treating patients with HBV-ACLF and to validate the Tongji prognostic predictor model (TPPM) in these patients.

Objective To compare the antiviral treatment situation between the elderly and young chronic hepatitis C (CHC) patients,and to discuss the influence factors of antiviral outcome in patients with chronic hepatitis C.Methods We retrospectively investigated 48 cases of chronic hepatitis C patients.They were divided into elderly patients (≥60 years,n =16) and young patients (＜60 years,n =32).After interferon plus ribavirin combination antiviral therapy,we observed virological response,biochemical response and adverse effects incidence in the two groups,and analyzed the antiviral outcome of possible factors.Results The rates of rapid virological response (RVR),early virological response (EVR) and sustained virological response (SVR) were 93.75％ (15/16),100.00％ (16/16),50.00％ (8/16)respectively in elderly patients.The rates of RVR,EVR and SVR were 90.63％ (29/32),100.00％ (32/32),78.13％ (25/32) respectively in young patients.There were significant differences in SVR rate between the two groups (P ＜ 0.05).Compared with the younger patients,the incidence of fatigue,neutropenia and anemia increased in elderly patients [93.75％ (15/16) vs 59.38％ (19/32),87.50％ (14/16) vs 53.13％ (17/32),56.25％ (9/16) vs 21.88％ (7/32)] (P ＜0.05).There were no significant differences in biochemical response and other adverse effects incidence between the two groups (P ＞ 0.05).The SVR rates and peg-interferon plus ribavirin antiviral treatment in young patients were higher than elderly patients and ordinary interferon plus ribavirin antiviral treatment patients respectively [78.12％ (25/32) vs 50.00％(8/16),80.00％ (28/35)vs 38.46％ (5/13)] (P ＜ 0.05).Conclusions The SVR rate of elderly CHC patients decreases significantly and the adverse effects incidence is high.The age and treatment options are related to antiviral outcome in patients with chronic hepatitis C.

目的 研究丙型病毒性肝炎肝硬化患者抗病毒治疗耐受及应答情况,探讨丙型肝炎抗病毒疗效的影响因素.方法 收集慢性丙型肝炎患者52例,其中肝硬化患者13例,菲肝硬化患者39例,均给予干扰素(IFN)联合利巴韦林抗病毒治疗后,观察两组患者病毒学应答、生化学应答及不良反应发生情况.结果 丙型肝炎肝硬化组平均年龄为(58.31±8.72)岁,非肝硬化组平均年龄为(36.95±15.30),两组比较差异无统计学意义(P＞0.05).肝硬化患者快速病毒学应答率(RVR)、早期病毒学应答率(EVR)和持续病毒学应答率(SVR)分别为84.62％、100.00％和53.85％,非肝硬化患者RVR、EVR和SVR分别为92.31％、100.00％和71.79％,两组比较差异均无统计学意义(P＞0.05).两组生化学应答比较差异均无统计学意义(P＞0.05).肝硬化组患者中性粒细胞减少、血小板减少和贫血的发生率均明显高于非肝硬化组,两组比较差异均有统计学意义(P＜0.05).肝硬化组患者中有2例出现白蛋白下降和腹水,其中1例中断治疗.老年(年龄≥60岁)和采用普通IFN联合利巴韦林抗病毒治疗的患者获得SVR率明显低于中青年患者(年龄＜60岁)和采用长效IFN联合利巴韦林抗病毒治疗的患者(P＜0.05).基因1型患者的SVR率低于非基因1型,但差异无统计学意义(P＞0.05).结论 代偿期丙型病毒性肝炎肝硬化患者多能耐受抗病毒治疗,且远期疗效较好.

Hepatitis B-related acute-on-chronic liver failure (ACLF) has a poor prognosis with very high mortality. Unfortunately, most prognostic predictive models of liver failure are complicated and offer suboptimal sensitivity. Experience in entecavir (ETV)-treated patients with hepatitis B virus (HBV)-ACLF is limited.

先证者,女,44岁,因原发性肝癌介入治疗术后半年,皮肤及巩膜黄染1个月余,腹胀半个月就诊.发病以来食欲减退,乏力,睡眠不佳,大便少,颜色灰白,小便茶色.既往史:患乙型病毒性肝炎十年,其余无异常.查体:T 36.1 ℃,P 72次/min,R 18次/min,BP 110/80 mm Hg,肝病面容,皮肤、巩膜黄染,未见肝掌、蜘蛛痣,心肺未见异常,腹平软,全腹无压痛,肝脾肋下未及,肝区无压痛、反跳痛,移动性浊音阳性,双下肢无浮肿.

Natural killer cells which functions are regulated by their receptors play crucial role in HCV infection and antiviral therapy.The recent research progress about NK cell receptors in HCV infection and antiviral therapy outcome are reviewed here.

Recently, Tupaia belangeri was used to study the full replication cycle of hepatitis B virus (HBV) in the primary hepatocyte cultures. Thus, the Tupaia model represents a suitable model to study the effects of cytokines on HBV infection. Here, Tupaia tumor necrosis factor-alpha (TNF-α) was molecularly cloned and expressed in mammalian cells. A test system for the biological activity of Tupaia TNF-α was established on the basis of its cytotoxic effect to the murine fibrosarcoma cell line L929. Recombinant Tupaia TNF-α was able to suppress HBV replication in primary Tupaia hepatocytes (PTH). However, the formation of HBV covalently closed circular DNA (cccDNA) and viral RNA was not completely prevented. Therefore, Tupaia TNF-α may contribute significantly to the control of HBV infection though it is not able to completely inhibit HBV replication alone. The characterization of this important cytokine allows further studies on its antiviral actions in the Tupaia model.

肝肾综合征(hepatorenal syndrome,HRS)是肝脏疾病患者在无肾脏原发病变的情况下发生的一种进行性功能性肾衰竭,主要见于有显著血液循环功能障碍的肝硬化腹水患者,也见于急性肝衰竭患者.HRS多由消化道出血、大量放腹水、过度利尿、自发性腹膜炎等诱发,病死率极高.

OBJECTIVE:To investigate the properties of HBsAb in occult hepatitis B virus infection and its affinity to different serotypes of hepatitis B virus surface antigen (HBsAg).METHODS:Long-term follow-up was conducted in 2 HBsAb positive patients with occult hepatitis B virus infection. HBsAg was detected using multiple diagnostic kits and the HBsAb subtype was determined by performing neutralization experiments with different serotypes of HBsAg. The viral S gene was PCR-amplified and mutation analysis was conducted. Plasmids expressing HBsAgs were constructed by inserting these PCR products into an eukaryotic expression vector and were then transfected into HepG2 cells. The cell culture supernatant and cellular extracts were detected for HBsAg respectively. Neutralization experiments were carried out in the cell culture supernatant from HBsAg plasmids transfected HepG2 cells and serum samples from these patients and others who had been confirmed to be positive for HBsAb.RESULTS:Multiple tests using various diagnostic kits showed that the 2 patients were negative for HBsAg and the three different serotypes of HBsAg (adr, adw, ay) could neutralize 82.1%-100% of HBsAb existed in the 2 patients. Sequence analysis of S gene cloned from these patients revealed that the homology to reference strain were 95.13%-97.79% and 92.04%-95.58% respectively at the nucleotide and amino acid levels. Quantitation of HBsAg showed that the expression levels of HBsAg from the two patients were 41.1% and 22.6% respectively of that of control HBsAg in cell culture supernatant and 48.1% and 59.3% respectively in cellular extract, and the supernatant/cell lysate ratios were 0.85 and 0.38 respectively. In neutralization experiments, HBsAg could be totally absorbed by control serum, whereas could only be partially neutralized by HBsAbs from the two patients (F = 353.6 and 645.2, P is less than 0.01).CONCLUSION:Both the antigenicity and the ability of HBsAg secreted outside of the cells are decreased in these HBsAb-positive patients with occult HBV infection. The HBsAbs are mainly specific for common epitopes among different serotypes of HBsAg and are probably different as compared with those produced by vaccine inoculation.