Peritoneal Level of CD206 Associates With Mortality and an Inflammatory Macrophage Phenotype in Patients With Decompensated Cirrhosis and Spontaneous Bacterial Peritonitis.
- 作者列表："Stengel S","Quickert S","Lutz P","Ibidapo-Obe O","Steube A","Köse-Vogel N","Yarbakht M","Reuken PA","Busch M","Brandt A","Bergheim I","Deshmukh SD","Stallmach A","Bruns T
BACKGROUND & AIMS:Peritoneal macrophages (PM) regulate inflammation and control bacterial infections in patients with decompensated cirrhosis. We aimed to characterize PM and associate their activation with outcomes of patients with spontaneous bacterial peritonitis (SBP). METHODS:We isolated PM from ascites samples of 67 patients with decompensated cirrhosis (20 with SBP) and analyzed them by flow cytometry, quantitative real-time PCR, functional analysis and RNA microarrays. We used ascites samples of a separate cohort of 120 patients with decompensated cirrhosis (76 with SPB) and quantified the soluble form of the mannose receptor (CD206) and tumor necrosis factor (TNF) by ELISA (test cohort). We performed logistic regression analysis to identify factors associated with 90-day mortality. We validated our findings using data from 71 patients with cirrhosis and SBP. Data from 14 patients undergoing peritoneal dialysis for end-stage renal disease, but without cirrhosis, were included as controls. RESULTS:We used surface levels of CD206 to identify subsets of large PM (LPM) and small PM (SPM), which differed in granularity and maturation markers, in ascites samples from patients with cirrhosis. LPM vs SPM from patients with cirrhosis had different transcriptomes; we identified more than 4000 genes that were differentially regulated in LPM vs SPM, including those that regulate the cycle, metabolism, self-renewal, and immune cell signaling. LPM had an inflammatory phenotype, were less susceptible to tolerance induction, and released more TNF than SPM. LPM from patients with cirrhosis produced more inflammatory cytokines than LPM from controls. Activation of PM by toll-like receptor agonists and live bacteria altered levels of CD206 on the surface of LPM and release of soluble CD206. Analysis of serial ascites fluid from patients with SBP revealed loss of LPM in the early phase of SBP, but levels increased after treatment. In the test and validation cohorts, patients with SBP and higher concentrations of soluble CD206 in ascites fluid (above 0.53 mg/L) were less likely to survive for 90 days than those with lower levels. CONCLUSIONS:Surface level of CD206 can be used to identify mature, resident, inflammatory PM in patients with cirrhosis. Soluble CD206 is released from activated LPM, and increased concentrations in patients with cirrhosis and SBP indicate reduced odds of surviving for 90 days.
背景与目的: 失代偿期肝硬化患者腹腔巨噬细胞 (PM) 调节炎症和控制细菌感染。我们旨在表征 PM，并将其激活与自发性细菌性腹膜炎 (SBP) 患者的结局相关联。 方法: 我们从 67 例失代偿期肝硬化患者 (20 例合并 SBP) 的腹水标本中分离 PM，并通过流式细胞术、实时定量 PCR 、功能分析和 RNA 芯片进行分析。我们使用了 120 例失代偿期肝硬化患者 (76 例 SPB) 的腹水样本，并定量了甘露糖受体 (CD206) 和肿瘤坏死因子 (TNF) 的可溶性形式通过 ELISA (测试队列)。我们进行了 logistic 回归分析，以确定与 90 天死亡率相关的因素。我们使用 71 例肝硬化和 SBP 患者的数据验证了我们的研究结果。将 14 例因终末期肾病接受腹膜透析但无肝硬化的患者的数据作为对照。 结果: 我们使用 CD206 的表面水平来鉴定肝硬化患者腹水样本中大 PM (LPM) 和小 PM (SPM) 的亚群，其粒度和成熟标志物不同。来自肝硬化患者的 LPM vs SPM 具有不同的转录组; 我们鉴定了 LPM vs SPM 中差异调控的 4000 多个基因，包括调控周期，代谢，自我更新的基因, 和免疫细胞信号。LPM 具有炎症表型，对耐受诱导不敏感，释放的 TNF 多于 SPM。来自肝硬化患者的 LPM 比来自对照组的 LPM 产生更多的炎症细胞因子。Toll 样受体激动剂和活菌对 PM 的激活改变了 LPM 表面 CD206 的水平和可溶性 CD206 的释放。对 SBP 患者连续腹水的分析显示，SBP 早期出现 LPM 丢失，但治疗后水平升高。在试验和验证队列中，SBP 和腹水中可溶性 CD206 浓度较高的患者 (高于 0.53 mg/L) 比水平较低的患者存活 90 天的可能性较小。 结论: CD206 表面水平可用于识别肝硬化患者的成熟、住院、炎性 PM。可溶性 CD206 由活化的 LPM 释放，肝硬化和 SBP 患者浓度增加表明存活 90 天的几率降低。
METHODS:BACKGROUND:Opioids are often prescribed for pain in cirrhosis and may increase the risk of hepatic encephalopathy (HE). AIMS:To assess the association between opioids and HE in patients with well-compensated cirrhosis. METHODS:We used the IQVIA PharMetrics (Durham, NC) database to identify patients aged 18-64 years with cirrhosis. We excluded patients with any decompensation event from 1 year before cirrhosis diagnosis to 6 months after cirrhosis diagnosis. Over the 6 months after cirrhosis diagnosis, we determined the duration of continuous opioid use and classified use into short term (1-89 days) and chronic (90-180 days). We assessed whether patients developed HE over the subsequent year (ie 6-18 months after cirrhosis diagnosis). We used a landmark analysis and performed multivariable Cox proportional hazards regression to assess associations between opioid use and HE, adjusting for relevant confounders. RESULTS:The cohort included 6451 patients with compensated cirrhosis, of whom 23.3% and 4.7% had short-term and chronic opioid prescriptions respectively. Over the subsequent year, HE occurred in 6.3% patients with chronic opioid prescriptions, 5.0% with short-term opioid prescriptions and 3.3% with no opioid prescriptions. In the multivariable model, an increased risk of HE was observed with short-term (adjusted hazard ratio, HR 1.44, 95% CI 1.07-1.94) and chronic opioid prescriptions (adjusted HR 1.83, 95% CI 1.07-3.12) compared to no opioid prescriptions. CONCLUSION:In this national cohort of privately insured patients with cirrhosis, opioid prescriptions were associated with the risk of incident HE. Opioid use should be minimised in those with cirrhosis and, when required, limited to short duration.
METHODS:BACKGROUND AND AIMS:Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS:We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS:Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS:We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.
METHODS:BACKGROUND:Spontaneous bacterial peritonitis (SBP) is a serious complication in patients with liver cirrhosis. In recent years, it has been postulated that the rate of multidrug-resistant organisms (MDROs) is increasing, especially in nosocomial SBP patients. Aim of the present work was to investigate this hypothesis and its possible clinical consequences. MATERIALS AND METHODS:One hundred and three culture-positive patients between 2007 and 2014 were compared with 81 patients between 2015 and 2017, to study the change of microbiological profiles and their clinical consequences. The cirrhosis patients with bacterascites requiring treatment were included as well. RESULTS:The most prevalent Gram-negative bacteria isolated from ascites were Enterobacterales (31.6%) and in Gram-positive pathogens Staphylococci (22.8%). There was a significant increase in MDROs (22.3% ICU 40.7%, P = .048), accompanied by an increased incidence of sepsis (from 21.4% to 37.0%, P = .021), hepatorenal syndrome (from 40.8% to 58.0%, P = .007) and the need of catecholamine therapy (from 21.4% to 38.8%, P = .036). Nosocomial origin correlated with higher MDRO proportion, more complications and lower antimicrobial susceptibility rates in 12 commonly used antibiotics. MDROs were confirmed as an isolated predictor for inpatient mortality and complications in multivariable logistic regression. CONCLUSIONS:The feeling in clinical practice that MDROs have increased in the last 11 years could be confirmed in our study in Munich, Germany. Nosocomial SBP correlated with significantly higher MDRO rates (nearly 50%) and complication rates. In our opinion, an antibiotic combination with comprehensive effect should be taken into account in nosocomial SBP patients in this region.