Decreased serum DNase1-activity in patients with autoimmune liver diseases

Deoxyribonuclease1 (DNase1) is involved in chromatin degradation of apoptotic cells. Its deficiency results in accumulation of self-DNA, which in turn may induce inflammation and autoimmunity. We assessed for the first time serum DNase1-activity in a large consecutive cohort of treatment-naïve patients with autoimmune liver diseases (ALD). DNase1-activity was determined by single radial enzyme-diffusion (SRED) at diagnosis of 224 patients with autoimmune hepatitis (AIH), 249 with primary biliary cirrhosis (PBC) and 36 with primary sclerosing cholangitis (PSC). Sera from 146 patients with chronic hepatitis B or C, 140 with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) and 114 healthy individuals served as disease and healthy controls. Available serum samples during remission from 50 AIH and 39 PBC patients were also investigated by paired analyzes. DNase1-activity was significantly lower in AIH, PBC and PSC compared to viral hepatitis (p?p?p?=?0.03), NAFLD/NASH (p?p?p?p?1400?mg/dl; p?p?p?p?=?0.008). In PSC, DNase1-activity was inversely associated with alkaline phosphatase (ALP) (p?p?p?相似文献   

Lipoteichoic acid may affect the pathogenesis of bile duct damage in primary biliary cirrhosis

Aim: Intrahepatic bile ducts are the targets for inflammation in primary biliary cirrhosis (PBC), but their pathogenesis is not known. Gram-positive bacterial DNA was detected recently in gallbladder bile of PBC patients. In the present study, we assessed the possible pathological role of lipoteichoic acid (LTA), the Gram-positive bacterial cell wall component, in PBC.

Methods: Liver samples, obtained from 20 patients with PBC (stage 1–2 with CNSDC: stage 3–4 with loss of bile ducts = 10:10) and from 13 patients with chronic hepatitis due to hepatitis C virus (CH–C) with lymphocytic cholangitis, were subjected to immunohistochemical staining with polyclonal rabbit anti-LTA as the primary antibody. Serum reactivities to LTA were studied by ELISA. After 1 μg of purified LTA was placed in a 96-well microplate as an antigen, an antibody capture assay was carried out using serum samples from PBC (n = 20), CH–C (n = 13) and healthy subjects (n = 11).

Results: LTA was localized around the sites of chronic non-suppurative destructive cholangitis (CNSDC) in the portal area in stage 1–2 PBC but was not detected in the portal area in CH–C. In stage 3–4 PBC, LTA was localized around sites of ductular proliferation at the periphery of portal tracts. IgM class anti-LTA serum titers were significantly higher in PBC than in CH–C. IgA class anti-LTA serum titers were significantly higher in PBC than in healthy subjects.

Conclusions: In the PBC livers, the profile of immunoreactivity to LTA changed markedly as the disease progressed. Sera from PBC showed higher levels of anti-LTA titers than CH–C (IgM) or from healthy subjects (IgA). The LTA-mediated immune system might affect the initiation and/or progression of PBC.     

Mechanism of autoimmune hepatic fibrogenesis induced by an adenovirus encoding the human liver autoantigen cytochrome P450 2D6

Autoimmune hepatitis type 2 (AIH-2) is a severe autoimmune liver disease with unknown etiology. We recently developed the CYP2D6 mouse model for AIH-2, in which mice are challenged with an adenovirus (Ad-2D6) expressing human cytochrome P450 2D6 (hCYP2D6), the major autoantigen in AIH-2. Such mice develop chronic hepatitis with cellular infiltrations and generation of hCYP2D6-specific antibodies and T cells. Importantly, the CYP2D6 model represents the only model displaying chronic fibrosis allowing for a detailed investigation of the mechanisms of chronic autoimmune-mediated liver fibrogenesis. We found that hCYP2D6-dependent chronic activation of hepatic stellate cells (HSC) resulted in an increased extracellular matrix deposition and elevated expression of α-smooth muscle actin predominantly in and underneath the liver capsule. The route of Ad-2D6 infection dramatically influenced the activation and trafficking of inflammatory monocytes, NK cells and hCYP2D6-specific T cells. Intraperitoneal Ad-2D6 infection caused subcapsular fibrosis and persistent clustering of inflammatory monocytes. In contrast, intravenous infection caused an accumulation of hCYP2D6-specific CD4 T cells throughout the liver parenchyma and induced a strong NK cell response preventing chronic HSC activation and fibrosis. In summary, we found that the location of the initial site of inflammation and autoantigen expression caused a differential cellular trafficking and activation and thereby determined the outcome of AIH-2-like hepatic damage and fibrosis.     

Novel insights into autoimmune liver diseases provided by genome-wide association studies

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are complex disorders, resulting from the interaction of genetic and environmental factors. For many years, investigators have attempted to delineate the genetic architecture of these conditions, aiming to elucidate disease pathogenesis and identify molecular targets for pharmacotherapy. Early genetic studies consisted of HLA association studies and non-HLA candidate gene association studies, designed to identify association with selected HLA or non-HLA loci. HLA association studies identified HLA risk loci that are now well-established. Non-HLA candidate gene studies were less fruitful because they were mostly underpowered to detect modest effects and were frequently designed to investigate one or two functional polymorphisms, meaning that gene coverage was poor. Furthermore, weak associations detected in one small cohort were often never validated. If replication studies were undertaken, the results were often conflicting. More recently, a series of genome-wide association studies (GWAS) and related study designs have evaluated the impact of common genetic variants (frequency >5% in the general population) across the entire genome. These studies have identified several non-HLA risk loci for autoimmune liver disease. The majority of risk loci detected are similar to those of non-hepatic immune-mediated diseases, suggesting that outcomes from GWAS and related genetic studies reflect broad phenotypic themes rather than traditional clinical conditions. The specific genetic basis of these PBC and PSC associated inflammatory themes as determined by GWAS is described and discussed in the context of interacting genetic and non-genetic (including environmental) factors.     

Hilar cholangiocarcinoma with extensive immunoglobulin G4 reaction

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic fibroinflammatory disorder that can involve multiple organs. It is often challenging to distinguish IgG4-related sclerosing cholangitis (IgG4-SC) from cholangiocarcinoma because of overlap in their clinical findings. A 75-year-old man presented to a hospital for a detailed examination of the elevation of some biliary enzymes. Radiographic examination revealed segmental bile duct with wall thickening of the common hepatic bile duct, and dilation of the peripheral branches. Transampullary biopsy showed a non-specific inflammatory reaction with several IgG4-positive cell infiltrations. There were no signs of malignancy. The liver biopsy showed bile duct injury accompanied by IgG4-positive cell infiltration. We then performed bile duct biopsy and finally diagnosed the patient with cholangiocarcinoma. We should remember that the IgG4 reaction is neither completely sensitive nor specific for IgG4-RD and avoid resting solely on the IgG4 reaction to precisely distinguish IgG4-SC from cholangiocarcinoma.     

Aeromonas sobria necrotizing fasciitis complicating neonatal sclerosing cholangitis

Aeromonas species can cause gastroenteritis, soft tissue infections, hepatobiliary tract and other infections. While most reported soft tissue infections have been attributed to Aeromonas hydrophila, we report a case of necrotizing fasciitis caused by Aeromonas veronii biovar sobria. Prompt and accurate diagnosis cum treatment could help save children with Aeromonas soft tissue infections from developing a bacteremia with extended morbidity and mortality.     

胆管炎与肝外胆管癌的多层螺旋CT诊断

目的:评价多层螺旋CT(Multi-slice computed tomography,MSCT)诊断胆管炎和肝外胆管癌的价值。材料和方法:对30例表现为梗阻性黄疸患者,经临床随访、ERCP和手术病理证实为胆管炎(10例)和胆管癌(20例)。MSCT检查上腹部,观察常规和薄层三维重建(MPR、MIP、CPR)图像,判断有无胆管扩张、胆管内或肝门区肿块、胆管壁局限增厚、肝脏有无直接侵犯征象,做出胆管炎或胆管癌诊断。结果:MSCT诊断胆管炎和肝外胆管癌的平均符合率为89.9%。胆管壁局限增厚对鉴别胆管炎和胆管癌具有重要意义。胆管内或肝门区肿块、肝脏直接侵犯征象诊断胆管癌的灵敏度为100%,阳性预测值分别为20%和25%。结论:MSCT结合薄层三维重建可较准确诊断胆管炎和肝外胆管癌。胆管壁局限增厚是肝外胆管癌的较特征性CT征象。     

丹参对急性梗阻性化脓性胆管炎患者术后肝功能的影响

目的 观察丹参对急性梗阻性化脓性胆管炎患者机体一期术后肝脏功能变化的影响。方法 将梗阻性急性化脓性胆管炎患者分为对照组及术后12h应用丹参治疗组,分别测定其手术前后外周血水平ALT、Tbil、肿瘤坏死因子(TNF)及透明酯酸(HA)水平变化。结果 治疗组自术后48h始ALT、Tbil、TNF及HA水平均显著低于对照组(P<0.05)。结论术后早期应用丹参有利于急性梗阻性化脓性胆管炎患者肝脏功能的恢复。     

超声引导PTCD在急性梗阻性化脓性胆管炎的应用价值

目的探讨急性梗阻性化脓性胆管炎的治疗方法,床旁急诊超声引导经皮肝穿刺胆道引流术(percutaneous transhepatic cholangial drainage,PTCD)在该病中的应用价值。方法收集2011年5月至201 5年6月海南省农垦总医院63例急性梗阻性化脓性胆管炎病人的临床资料,回顾分析床旁急诊超声引导PTCD的治疗效果。结果超声引导PTCD成功率为100%;引流量为250~830 ml/d,平均为(530±68)ml/d;引流后血常规及肝功能检查结果显示,与术前比较,白细胞计数(WBC)、血清总胆红素(TBIL)、血清直接胆红素(DBIL)、丙氨酸转氨酶(ALT)指标显著下降,血小板计数(BPC)上升,体温正常,差异均有统计学意义(P0.01)。症状改善58例(92%),死亡5例(8%),无引流管脱落,无腹腔内出血、胆道出血、气胸、胆漏等并发症发生。结论床旁急诊超声引导PTCD,能快速有效引流,操作方便、简单,创伤小,并发症少,安全性高,能为解除病因手术安全性创造条件。