T1846 and A/G1913 are associated with acute on chronic liver failure in patients infected with hepatitis B virus genotypes B and C

The aim of this study was to determine whether mutations in the hepatitis B virus (HBV) genome are associated with the onset of acute on chronic liver failure (ACLF). For the longitudinal study, full‐length HBV genomes were cloned and sequenced from four ACLF patients and compared with sequences from matching samples collected before ACLF. For the cross‐sectional study, 166 serum samples were obtained, including 49 samples from patients with ACLF. The results of longitudinal study showed that C53T, A1846T, and G1896A were the most common mutations in association with ACLF. In the cross‐sectional study 61.2% patients with ACLF presented with T1846, which was higher than patients with chronic hepatitis B (CHB) (11.1%), liver cirrhosis (LC) (31.1%), and hepatocellular carcinoma (HCC) (33.3%). Prevalence of A/G1913 was 42.9% in patients with ACLF, also higher than patients with CHB (2.2%), LC (17.8%), and HCC (11.1%). There were no differences in HBV genotype and patients' HBeAg status among patients with ACLF, LC, and HCC. However, prevalence of T1846 was much higher in patients infected with genotype B (57.1%) than genotype C (30.4%). A/G1913 was higher in HBeAg negative patients (28%) than HBeAg positive patients (13.2%). Results of a multivariable analysis showed that T1846 and A/G1913 were independent factors for ACLF (OR = 3.373 and 4.244, respectively). Interestingly, T1846 destroys an ATG codon of a small open reading frame in the preC region, which may increase core protein expression. We conclude that T1846 and A/G1913 in the preC/C gene are closely associated with ACLF. J. Med. Virol. 83:996–1004, 2011. © 2011 Wiley‐Liss, Inc.     

Regulation of Toll-like receptor (TLR)2 and TLR4 on CD14dimCD16+ monocytes in response to sepsis-related antigens

Rapid overproduction of proinflammatory cytokines are characteristic of sepsis. CD14(dim)CD16(+) monocytes are thought to be major producers of cytokine and have been shown to be elevated in septic patients. Toll-like receptors (TLR) are pattern recognition receptors important in mediating the innate immune response and their activation can lead to production of cytokines. Using whole blood culture and flow cytometry we have investigated TLR2 and TLR4 regulation after stimulation with sepsis-relevant antigens [lipopolysaccharide (LPS), Staphylococcal enterotoxin B (SEB) and peptidoglycan (PGN)]. The percentage of CD14(dim)CD16(+) monocyte population expanded at 20 h post-stimulation, after a rise in tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 at 2 h. A strong positive correlation between the percentage of CD14(dim)CD16(+) monocytes and secreted TNF-alpha was demonstrated (r = 0.72). Furthermore, we were able to induce expansion of the CD14(dim)CD16(+) population to approximately 35% of all monocytes with the addition of recombinant TNF-alpha to the whole blood culture. TLR4 was found to be expressed 2.5 times higher on CD14(dim)CD16(+) compared to CD14(+) CD16(-) monocytes, while TLR2 expression was similar in both subpopulations. The CD14(dim)CD16(+) and CD14(+) CD16(-) monocyte populations were different in their response to various antigens. LPS down-regulated TLR4 by 4.9 times in CD16(+) monocytes compared to only 2.3 times in CD16(-) monocytes at 2 h. LPS was able to up-regulate TLR2 by 6.2 times after 2 h, with no difference between the subpopulations. LPS further up-regulated TLR2 by 18.4 times after 20 h only in the CD14(+) CD16(-) population. PGN and SEB induced no significant changes in TLR2 or TLR4 expression. We hypothesize that following exposure to bacterial antigens, subsequent TNF-alpha drives a differentiation of monocytes into a CD14(dim)CD16(+) subpopulation.     

自身免疫性肝炎患者外周血CD16阳性单核细胞的特点及临床意义

目的 探讨自身免疫性肝炎(autoimmune hepatieis,AIH)患者外周血CD16阳性单核细胞的频率、表型特点及其临床意义.方法 选取白求恩国际和平医院全军肝病诊治中心2010年1月至2013年12月收治的初治AIH患者13例和健康对照8例作为研究对象,利用流式细胞术检测入组个体外周血CD16阳性单核细胞频率、膜分子人白细胞抗原DR(HLA-DR)、Toll样受体(toll like receptor,TLR)-2、TLR-4的表达特点及肿瘤坏死因子(tumornecrosis factor,TNF)-α的分泌能力.结果 AIH组外周血CD16阳性单核细胞频率明显升高,组间比较差异有统计学意义(Z=-2.028,P<0.05).AIH患者外周血CD16阳性单核细胞频率与血浆天冬氨酸氨基转移酶(aspartate aminotransferase,AST)水平呈显著正相关(r=0.573,P<0.05).AIH患者CD16阳性单核细胞表达HLA-DR较健康对照组明显降低(Z=-2.173,P<0.05),而TLR-4表达(Z=-1.992,P<0.05)和TNF-α的分泌能力明显升高(Z=-2.607,P<0.05),组间比较差异均有统计学意义.联合治疗后CD16阳性单核细胞频率明显降低(Z=-2.197,P<0.05),HLA-DR的表达水平升高(Z=-2.366,P<0.05),而TLR-4水平则显著降低(Z=-2.197,P<0.05),均有统计学意义.结论 CD16阳性单核细胞可能参与了AIH的发病机制并与肝组织炎症和坏死有关.     

Presence of valine at position 27 of the hepatitis B virus core gene is associated with severe liver inflammation in Chinese patients

Although it is widely believed that cytotoxic T lymphocytes (CTL) are responsible for severe flares of chronic hepatitis B that lead to liver failure, the published evidence to support this hypothesis is weak. The frequency of the I27V mutation in the HBV core gene, which produces a core 18–27 peptide capable of binding HLA‐A*02, was compared in Chinese patients with severe liver inflammation (n = 77, including 39 with acute‐on‐chronic liver failure), moderate liver inflammation (n = 44) and inactive disease (n = 45). The frequency with which V27 reverted to the wild‐type I27 was compared in severe liver inflammation patients who were either HLA‐A*02 positive (n = 5) or negative (n = 5). The frequency of patients with a V27 positive HBV was higher in severe than in moderate liver inflammation (23.4% vs. 6.8%, P = 0.02) or inactive disease (23.4% vs. 4.7%, P = 0.006). After a minimum of 3 months follow‐up, the frequency of reversion of V27 to the wild‐type I27 was higher in HLA‐A*02 positive than negative patients (5/5 vs. 1/5, P = 0.05). In summary, this is the first data showing an association between a specific amino acid mutation (I27V) and severe liver inflammation in patients with chronic hepatitis B. This mutation would produce a peptide that is known to bind HLA‐A*02 and stimulate CTL. The high frequency of reversion to wild‐type I27 in HLA‐A*02 positive subjects suggests that CTL recognizing this peptide exist, and is consistent with the possibility that they contribute to the pathophysiology of severe liver inflammation in chronic hepatitis B. J. Med. Virol. 83:218–224, 2011. © 2010 Wiley‐Liss, Inc.     

Quantification of cerebral edema on diffusion tensor imaging in acute-on-chronic liver failure

Cerebral edema is a major complication of acute liver failure but may also be seen in other forms of liver failure such as acute-on-chronic liver failure (ACLF) and chronic liver failure (CLF). ACLF develops in patients with previously well-compensated chronic liver disease following acute hepatitis A or E superimposed on underlying liver cirrhosis. The aim of this study was to detect the occurrence, and determine the nature, of cerebral edema in patients with the defined subset of ACLF using diffusion tensor imaging (DTI) metrics. Twenty-three patients with ACLF were studied and compared with 15 healthy controls and 15 patients with CLF. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), linear anisotropy (CL), planar anisotropy (CP), and spherical isotropy (CS) were calculated by selecting regions of interest in the white matter and deep grey matter of the brain. Significantly decreased FA and increased CS were observed in the anterior limb (ALIC) and posterior limb (PLIC) of the internal capsule and frontal white matter (P<0.05) in patients with different grades (1-4) of ACLF when compared with healthy controls. No significant changes in MD and CP were seen in any brain region. However, significantly decreased CL was observed in the PLIC, caudate nuclei and putamen. In patients with CLF, significantly decreased FA with increased CS in the ALIC and PLIC along with significantly increased MD in the ALIC and caudate nuclei were observed. The presence of significantly decreased FA and CL and increased CS along with no significant change in MD and CP suggests the presence of both intracellular and extracellular components of cerebral edema in patients with ACLF.     

Altered innate immune response of plasmacytoid dendritic cells in multiple sclerosis

Plasmacytoid dendritic cells (pDCs) are of crucial importance in immune regulation and response to microbial factors. In multiple sclerosis (MS), pDCs from peripheral blood showed an immature phenotype, but its role in susceptibility to MS is not determined. Because infectious diseases are established triggers of exacerbations in MS, in this study we have characterized the expression of Toll‐like receptors (TLR) and the maturation and functional properties of peripheral blood pDCs from clinically stable, untreated MS patients in response to signals of innate immunity. After stimulation of TLR‐9, interferon (IFN)‐α production by pDCs was significantly lower in MS (n = 12) compared to healthy controls (n = 9). In an allogenic two‐step co‐culture assay we found an impaired effect of TLR‐9 stimulation on IFN‐γ expression of autologous naive T cells in MS patients (n = 4). In peripheral blood mononuclear cells, TLR‐9 stimulation with type A CpG ODN resulted in a higher expression of TLR‐1, ‐2, ‐4, ‐5 and ‐8 in MS patients (n = 7) compared with healthy controls (n = 11). These findings suggest an altered innate immune response to microbial stimuli in MS patients and may help understanding of why common infectious agents trigger MS attacks.     

Hepatitis B virus genotype B with G1896A and A1762T/G1764A mutations is associated with hepatitis B related acute-on-chronic liver failure

The existence of statistical associations between hepatitis B‐related acute‐on‐chronic liver failure and both hepatitis B virus (HBV) genotype and mutations in the basal core promoter (BCP) and precore (PC) regions needs to be confirmed. A total of 322 patients with a chronic HBV infection, including 77 with hepatitis B‐related acute‐on‐chronic liver failure, 109 with hepatocellular carcinoma (HCC) and 136 with chronic hepatitis B (CHB) were enrolled. The HBV genotype and the presence of mutations in the BCP/PC regions were determined by direct sequencing, and the frequencies were compared in the three patient groups. Overall, 198/322 (61.5%) were infected with genotype B and 124/322 (38.5%) with genotype C. Genotype B was significantly more frequent in patients with acute‐on‐chronic liver failure than CHB (92.2% vs. 60.3%, P < 0.001). As a contrast, genotype C was more common in patients with HCC than CHB (58.7% vs. 39.7%, P = 0.003). In genotype B patients, the A1762T/G1764A, A1846T, and G1896A mutations were significantly more prevalent in patients with acute‐on‐chronic liver failure than CHB (50.7% vs. 28.0%, P = 0.004; 59.2% vs. 34.1%, P = 0.002; 69.0% vs. 41.5%, P = 0.001, respectively). In multivariate analysis, the risk factors for acute‐on‐chronic liver failure were genotype B, A1762T/G1764A, and G1896A. In conclusion, CHB patients with genotype B, G1896A, and A1762T/G1764A had a higher tendency to develop liver failure than patients with genotype C. Therefore, HBV genotyping and detecting G1896A and A1762T/G1764A mutations might have important clinical implications as predictive risk factors for hepatitis B‐related acute‐on‐chronic liver failure. J. Med. Virol. 83:1544–1550, 2011. © 2011 Wiley‐Liss, Inc.     

TLR4 upregulation underpins airway neutrophilia in smokers with chronic obstructive pulmonary disease and acute respiratory failure

Activation of Toll-like receptors (TLR) seems to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Upon TLR activation the release of defensins, including human beta defensin 2 (HBD-2), may occur. In this study, we explored the innate responses in patients with respiratory failure, with and without COPD, requiring intubation and mechanical ventilation. Mini-bronchoalveolar lavage (mini-BAL) samples were collected from nonsmoker subjects without COPD (n = 10), smokers without COPD (n = 6), and smokers with COPD (n = 15). TLR4, TLR2, and HBD-2 expression was evaluated by immunocytochemistry; interleukin (IL)-8, IP-10, and HBD-2 concentrations were evaluated by enzyme-linked immunosorbent assay; chemotactic activity toward neutrophils and lymphocytes; and cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL] and by flow cytometry with anti-TLR4 and with HBD-2 depleted and not depleted mini-BAL). COPD mini-BAL showed increased neutrophil numbers, reduced neutrophil apoptosis, increased TLR4 and HBD-2 expression, increased neutrophil chemotactic activity, reduced IP-10 concentrations, and reduced lymphocyte chemotactic activity compared with those in nonsmoker subjects without COPD. In the smokers without COPD the mini-BAL showed reduced TLR4 and HBD-2 expression, higher IP-10 concentrations, and higher chemotactic activity than in patients with COPD. The blocking of TLR4 activation and HBD-2 depletion increased neutrophil apoptosis. No differences were observed for TLR2 expression and IL-8 concentrations. This study strengthens the contribution of TLR4 to promoting airway neutrophilia in COPD.     

The characteristic expression of B7‐H3 and B7‐H4 in liver biopsies from patients with HBV‐related acute‐on‐chronic liver failure

Hepatitis B virus (HBV) is a major public health problem, and HBV‐related acute‐on‐chronic liver failure (HBV‐ACLF) has an extremely poor prognosis due to a lack of effective treatments. B7‐H3 and B7‐H4 are two novel members of the B7 superfamily that are actively involved in regulating the pathogenesis of infectious diseases. However, the intrahepatic expression of both members in HBV‐ACLF patients has yet to be described. In this study, we analyzed the expression of B7‐H3 and B7‐H4 in HBV‐ACLF biopsies by immunohistochemistry. Our results showed that both members were observed in all HBV‐ACLF samples, and their expression was chiefly observed on infiltrating inflammatory cells and the damaged bile ducts. Immunofluorescence double staining showed that B7‐H4 was expressed chiefly on CD3⁺ T cells, CD68⁺ macrophages, CK‐18⁺ bile ducts, and CD31⁺ endothelial cells, while B7‐H3 was found on all cell types detected. The expression of the programmed death (PD)‐1 ligands, PD‐L1 and PD‐L2, was also detected in these liver tissues and they were found to be co‐expressed with B7‐H3 and B7‐H4. These results suggest that the B7‐family signaling is most likely to affect the pathogenesis of this disease, and a clear understanding of their functional roles may further elucidate the disease process.     

Toll样受体4及细胞因子在酒精性肝病发病机理中的作用

目的：探讨肝组织Toll样受体4（TLR4）和白细胞介素1β（IL-1β）、白细胞介素6（IL-6）、白细胞介素10（IL-10）及肿瘤坏死因子α（TNF-α）在酒精性肝病（ALD）发病机理中的作用。方法：应用酒精灌胃建立大鼠酒精性肝病模型,分别于4、8、12和16周末留取血清和肝组织,检测血清IL-1β、IL-6、IL-10及TNF-α含量,应用HE染色、苏丹Ⅳ染色和天狼星红染色观察肝组织病理形态,应用RT-PCR方法观察肝组织Toll样受体4 mRNA表达。结果：随着酒精性肝病病程进展,血清IL-1β、IL-6、IL-10、TNF-α含量逐渐升高（P〈0.05或P〈0.01）,肝组织Toll样受体4 mRNA表达明显增强（P〈0.05或P〈0.01）,IL-10于4、8周时明显升高而于12周后逐渐下降;TLR4相对表达量与IL-1β、IL-6、TNF-α含量呈正相关,与IL-10呈负相关（P〈0.05或P〈0.01）。结论：致炎因子和抗炎因子的表达失衡及Toll样受体4表达增强在酒精性肝病发病过程中发挥着重要作用。     

Children with atopic histories exhibit impaired lipopolysaccharide‐induced Toll‐like receptor‐4 signalling in peripheral monocytes

Background The hygiene hypothesis states that early exposure to bacterial products such as lipopolysaccharide (LPS) may be protective against the development of allergic diseases. Whether atopic disease affects the ability of immune cells to respond to LPS is unclear. Our laboratory has demonstrated previously that children express high levels of Toll‐like receptor (TLR)‐4 on CD4⁺ cells in nasal mucosa. Objective To determine if children with a history of allergic disease have impaired responses to LPS on circulating CD4⁺ leucocytes. Methods Peripheral blood mononuclear cells from children (aged 2–18) and adults with or without a history of atopic conditions were cultured with/without IL‐4 or LPS for up to 24 h. Expression of surface TLR‐4, CD14, CD4, CD3, as well as of intracellular phosphorylated ^p42/p44ERK and p38 mitogen‐activated protein kinase (MAPK) were assessed by flow cytometry. Results A history of atopy in children was associated with impaired LPS‐induced TLR‐4‐dependent phosphorylation of ^p42/44ERK and p38 MAPK by CD4⁺ monocytes. Decreased LPS signalling was reproduced by pre‐incubation of control cells with recombinant IL‐4. LPS stimulation also decreased TLR‐4 expression on monocytes from children without atopic histories but not from atopic subjects. CD4⁺ T lymphocytes showed limited LPS responsiveness, regardless of atopic status. In contrast with non‐atopic children, TLR‐4 expression on monocytes of children with atopic histories decreased as a function of age. Conclusions This study provides evidence for defective LPS recognition on circulating CD4⁺ leucocytes of subjects with atopic histories compared with those from non‐atopic children. CD4⁺TLR4⁺ monocytes from children with atopic histories failed to phosphorylate MAPKs. Our results suggest that a history of atopic disease is associated with impaired TLR‐4‐mediated innate immune function compared with non‐atopic children. Cite this as: D. Préfontaine, A.‐A. Banville‐Langelier, P.‐O. Fiset, J. Guay, J. An, M. Mazer, Q. Hamid and B. D. Mazer, Clinical & Experimental Allergy, 2010 (40) 1648–1657.     

Expression of TLR 2, TLR 4 and iNOS in cervical monocytes of Chlamydia trachomatis-infected women and their role in host immune response

Citation Agrawal T, Bhengraj AR, Vats V, Salhan S, Mittal A. Expression of Toll‐like receptors (TLR) 2, TLR 4 and inducible nitric oxide synthase (iNOS) in cervical monocytes of Chlamydia trachomatis‐infected women and their role in host immune response. Am J Reprod Immunol 2011; 66: 534–543 Problem To study the innate immune response ‐TLR2 TLR 4 and iNOS expression in female genital Chlamydia trachomatis infection. Method TLR 2, TLR 4, and iNOS expression was evaluated by real‐time PCR in C. trachomatis‐infected asymptomatic, mucopurulent cervicitis (MPC), and fertility disorders (FD) women. Expression of TLR signaling pathway genes was checked in vivo in C. trachomatis‐infected cervical monocytes. Further, inos gene expression and nitric oxide release was assessed in vitro in THP‐1 cell line upon chlamydial infection. Results TLR2, TLR4, and iNOS expression was significantly (P < 0.05) higher in C. trachomatis‐positive women with FD, MPC, and asymptomatic women, respectively, than in control. Chlamydial infection significantly upregulates CD86, TLR4, MyD88, IRAK2, nF‐κB, IL‐1,β and IL‐12 genes. Expression of iNOS gene was found to be significantly (P < 0.05) high 12 hrs post‐infection. Conclusions Chlamydia trachomatis stimulates innate immune cells by activation of TLR2/TLR 4. Overall data indicate that recognition by TLR4 helps in initiation of immune response while recognition by TLR2 leads to secretion of inflammatory cytokines while iNOS‐induced nitric oxide production helps in clearing Chlamydia. These results are first to provide initial insights into how innate immune response operates in human cervical monocytes upon chlamydial infection.     

Gender and ethnic differences in the post-liver transplant outcomes of patients with autoimmune hepatitis with acute liver failure at initial presentation: a case-control study

Introduction

Autoimmune hepatitis (AIH) may initially present as acute liver failure (ALF). The outcome of liver transplantation (LT) in patients with AIH and ALF is not very well defined. We determined the outcome of LT in UNOS (United Network for Organ Sharing) status 1 adult patients with and without AIH using post-MELD (Model for End-Stage Liver Disease) UNOS data.

Material and methods

For each AIH patient, 3 patients with non-AIH, matched for age ±5 years and donor risk index (DRI) ±5 years, were identified; 200 patients (50 AIH, 150 non-AIH) were found eligible for the study.

Results

Patients with AIH were more likely to be female (p = 0.003), non-Caucasian (p = 0.009), have higher bilirubin (p = 0.003), longer waiting time (p = 0.01), and lower creatinine (p = 0.019). African American patients with AIH were younger (p = 0.003), had lower bilirubin (p = 0.037), and were more likely to have had a prior LT compared to Caucasians (p = 0.02). Kaplan-Meier analysis showed that 5-year post-LT survival was similar in those with and without AIH (p = 0.3). African American with AIH showed a trend for lower 5-year survival compared to Caucasians (55% vs. 80%, p = NS). Women had a better outcome, especially in those with non-AIH (p = 0.002).

Conclusions

Patients with AIH transplanted as status 1 have similar outcomes to those without AIH. Women with non-AIH-related ALF have better survival than their male counterparts.     

Dysregulation of toll‐like receptor (TLR) 2 expression on monocytes and upregulation of the frequency of T cells expressing TLR2 in patients with chronic hepatitis C virus infection

Toll‐like receptors (TLRs) initiate inflammatory responses that may play a role in disease progression in patients infected with hepatitis C virus (HCV). TLR2 and TLR4 surface expression were assessed on CD14⁺ monocytes, CD4⁺ and CD8⁺ T cells in treatment naïve patients with chronic HCV infection with fibrosis, without fibrosis, co‐infected with human immunodeficiency virus (HIV), and in healthy controls. Increased expression of TLR2 was found on monocytes in HCV‐infected patients with fibrosis (p < 0.01), co‐infected with HIV (p = 0.03), and possibly in patients without fibrosis (p = 0.07) when compared to controls. TLR2 positive CD4⁺ and CD8⁺ T cells were upregulated in patients with fibrosis only (p < 0.01). However, expression of TLR2 was not associated with T cell activation. TLR4 expression was similar in patients and healthy controls. In conclusion, TLR2 expression on monocytes and the frequency of T cells expressing TLR2 may contribute to disease progression in chronic HCV infection.     

Assessment of erythropoietin levels and some iron indices in chronic renal failure and liver cirrhosis patients

This study was constructed to investigate the relationship between renal anaemia and erythropoietin (EPO) concentrations in chronic renal failure (CRF) patients and to evaluate the possible role of the liver. Serum EPO levels were measured in blood samples from 20 CRF patients on hemodialysis (HD), 20 liver cirrhosis (LC) patients, 20 patients having both CRF and LC and undergoing HD, and 20 normal control subjects. Blood cell counts, iron indices (iron, total iron-binding capacity (TIBC) and ferritin), renal function (blood urea nitrogen (BUN) and creatinine), hepatic function (ALT, AST, ALP and bilirubin) investigations were carried out for all the subjects enrolled in this study. CRF patients without LC had serum EPO concentration of 6.21 +/- 0.53 mU/ml (mean +/- SE), which was significantly higher than that in patients having both CRF and LC (4.32 +/- 0.52) (p < 0.01). Both groups showed significantly lower values than the controls (12.75 +/- 0.70) (p < 0.001). LC patients with intact kidneys had significantly higher EPO level (22.70 +/- 1.70) (p < 0.001). No correlation was found between EPO level and any of the hematologic or iron indices.     

Hyper-IL-6重组腺病毒治疗大鼠急性肝衰竭的实验研究

目的 探讨重组腺病毒介导的超级白细胞介素6(Hyper-IL-6)对大鼠急性肝衰竭的治疗作用及机制.方法 80只急性肝衰竭模型大鼠随机分为:未感染组、AdO组、AdlL-6组、AdHIL-6组,分别予腹腔注射生理盐水、AdO、AdIL-6、AdHIL-6,后进行肝功能指标、肝脏病理学及肝细胞原位凋亡检测,并观察增殖细胞核抗原(PCNA)、caspase-3在肝组织中的表达情况及大鼠14 d存活率.结果 AdHIL-6组血清丙氨酸氨基转移酶(ALT)、总胆红素(TB)含量及凋亡指数明显降低,而肝组织PCNA表达明显增高(P<0.01),肝组织病变减轻,caspase-3表达阳性,14 d存活率较高.结论 Hyper-IL-6对急性肝衰竭大鼠有明显的促肝细胞增殖及抗肝细胞凋亡效应,能有效改善肝功能及肝组织学状况,提高肝衰竭大鼠存活率.     

急性肝功能衰竭急诊肝移植围术期治疗的单中心经验探讨

背景：急性肝衰竭行急诊肝移植患者围手术期治疗的病情复杂,风险大,并发症多,死亡率高,与普通肝脏移植有着明显不同。 目的：总结急诊肝移植治疗急性肝功能衰竭的围手术期治疗经验,以提高急性肝功能衰竭的治疗成功率。 方法：回顾性分析38例因急性肝功能衰竭行急诊肝移植患者的临床资料,男21例,女17例,年龄15-69岁。其中乙型肝炎病毒性肝炎23例(其中乙型合并丁型肝炎2例),Wilsons病7例,3例为毒蕈中毒,2例不明原因药物肝脏损害,1例雷公藤多甙中毒,1例为外伤行肝脏部分切除后失代偿,1例尸体肝移植后患者。 结果与结论：38例患者生存时间为13-1 740 d,中位生存时间为634 d。患者的围手术期存活率为76%,1年存活率为63%,2年存活率为58%。9例围手术期死亡原因包括脑水肿及颅内高压、肾功能衰竭、严重肺部感染、多脏器功能衰竭、凝血功能障碍(颅内出血、上消化道出血等)、急性成人呼吸窘迫综合征、移植物原发性无功能。目前急诊肝移植仍是治疗急性肝功能衰竭最有效的方法,出血、感染、排异反应是死亡的主要原因,肝移植围手术期间每一环节的处理,对于肝移植的成功和患者长期存活具有重要意义。 中国组织工程研究杂志出版内容重点：肾移植;肝移植;移植;心脏移植;组织移植;皮肤移植;皮瓣移植;血管移植;器官移植;组织工程全文链接：     

急性肝功能衰竭小鼠肠屏障功能障碍的实验研究

目的探讨急性肝功能衰竭时肠屏障功能的变化。方法腹腔注射D-氨基半乳糖（D-GalN,700mg/kg）/内毒素（LPS,10μg/kg）建立小鼠急性肝功能衰竭模型,造模6h后测定小鼠血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）的活性,取肠内容物及肝组织进行细菌培养,同时检测肠组织二胺氧化酶（DAO）的活性。结果腹腔注射D-GalN/LPS6h后,小鼠血清中ALT、AST活性显著提高（P〈0.01）;肠道内肠杆菌、肠球菌数量明显上升（P〈0.01）,乳酸杆菌、双歧杆菌数量明显下降（P〈0.05）;肠组织DAO活性明显降低（P〈0.01）;肝脏细菌培养阳性率达100%。结论急性肝功能衰竭时肠屏障明显受损,并发生菌群失调及细菌易位。     

Human herpesvirus-6 infection: a prospective study evaluating HHV-6 DNA levels in liver from children with acute liver failure

The aim of this prospective study was to investigate the role of HHV-6 infection in children with acute onset of liver failure using real-time quantitative PCR. Twenty-three children (median age, 24 months) were included: 6 cases of fulminant hepatic failure of undetermined cause (group 1); 4 cases of fulminant hepatic failure of recognized cause (group 2); 3 cases of acute decompensation of chronic liver disease (group 3); and 10 cases of chronic liver disease (group 4). HHV-6 genomic DNA was detected and quantified using real-time PCR in plasma and livers obtained at the time of transplantation. HHV6-DNA detection rate was significantly higher among groups 1, 2, and 3 compared to group 4 (76.9% vs. 20% P = 0.02). Viral loads ranged from 6 to 32,500 copies/106 cells. Significantly higher viral loads were found in 4 of 9 children with acute onset of liver failure of unknown origin (group 1, n = 3; group 3, n = 1) and 1 child with fulminant autoimmune hepatitis (group 2) (P = 0.03). These results strongly support the hypothesis that HHV-6 may cause fulminant hepatic failure and acute decompensation of chronic liver disease in children. Nevertheless, a threshold viral load value still remains to be determined.