中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

Pathogen distribution and drug resistance in liver cancer patients with liver abscess after transarterial chemoembolization or ablation

DOI: 10.3969/j.issn.1001-5256.2020.01.026
  • Received Date: 2019-07-24
  • Published Date: 2020-01-20
  • Objective To investigate the pathogen distribution characteristics and drug resistance in patients with liver abscess after transarterial chemoembolization(TACE) or ablation for liver cancer,and to provide a basis for rational use of antibacterial agents in clinical practice. Methods A retrospective analysis was performed for the results of the strains isolated from liver pus and blood culture and drug sensitivity test of the liver cancer patients who were admitted to Beijing YouAn Hospital from January 2011 to December 2018 and developed liver abscess after TACE/ablation. The Chi-square test was used for comparison of categorical data between groups. Results A total of 49 patients were enrolled,with 15 in TACE group and 34 in ablation group. A total of 35 strains of pathogenic organisms were detected in the TACE group,and Gram-negative bacteria,Gram-positive bacteria,and fungi accounted for 54. 3%,40%,and 5. 7%,respectively; Klebsiella pneumoniae,Enterococcus faecium,and Pseudomonas aeruginosa were the main pathogenic bacteria isolated from liver pus culture,and Enterococcus faecalis,Escherichia coli,and Citrobacter were the main pathogenic bacteria isolated from blood culture. A total of 64 strains of pathogenic organisms were detected in the ablation group,and Gram-negative bacteria,Gram-positive bacteria,and fungi accounted for 59. 4%,39. 1%,and 1. 6%,respectively; Escherichia coli,Klebsiella pneumonia,and Enterococcus faecalis were the main pathogenic bacteria isolated from liver pus culture,and Klebsiella pneumoniae,Escherichia coli,and Enterococcus faecalis were the main pathogenic bacteria isolated from blood culture. Drug susceptibility results showed that in the strains of Klebsiella pneumoniae and Escherichia coli,the ESBL-producing strains accounted for 26. 3%(5/19) and 43. 8%(7/16),respectively,and the carbapenem-resistantstrains accounted for 10. 5%(2/19) and 12. 5%(2/16),respectively. Klebsiella pneumoniae had a drug resistance rate of ≤10. 5% to third-generation cephalosporins,quinolones,aminoglycosides,piperacillin/tazobactam,and carbapenems,and Escherichia coli had a drug resistance rate of 43. 8%-62. 5% to the tested cephalosporins,quinolones,and penicillins,18. 8% to piperacillin/tazobactam,and 12. 5%to carbapenems. In the strains of Enterococcus faecium and Enterococcus faecalis,the vancomycin-resistant strains accounted for 13. 3%(2/15) and 0,respectively,and the linezolid-resistant strains accounted for 13. 3%(2/15) and 28. 6%(2/7),respectively,while no teicoplanin-resistant strains were detected. Conclusion Klebsiella pneumoniae,Escherichia coli,Enterococcus faecium,and Enterococcus faecalis are the main pathogenic bacteria of liver abscess after TACE/ablation for liver cancer,and drugs should be selected based on drug susceptibility results to reduce drug-resistant strains.

     

  • 原发性胆汁性胆管炎(primary biliary cholangitis,PBC)旧称原发性胆汁性肝硬化,是一种慢性进行性胆汁淤积性肝病,其组织学特点是肝内小叶间胆管非化脓性肉芽肿性炎症,引起小叶间胆管消失,最终导致胆汁性肝纤维化,甚至胆汁性肝硬化和肝衰竭[1-2]。PBC的血清学特征是出现抗线粒体抗体(anti-mitochondrial antibody, AMA)2型。大部分的PBC患者为40岁以上的中老年女性,其中1/3的患者无任何症状,通常在常规体检中被发现。从出现症状时起,平均生存期为5~8年,早期诊治对预后起着关键作用[3-5]。目前治疗PBC的主要药物为熊去氧胆酸(ursodeoxycholic acid,UDCA),经大量的临床研究证实,UDCA可明显改善多数PBC患者的肝功能,有效延缓病情进展从而延长生存时间。但是仍有约25%~40%的PBC患者对UDCA应答不佳[6],部分应答不佳的患者,根据需要改用或者加用二线治疗药物如奥贝胆酸、免疫抑制剂或布地奈德等则可以取得良好的疗效[7-10]。在评估PBC患者对UDCA等药物的应答情况方面,肝组织病理学比血清生化学更能准确地反应出用药以来的病情变化[11]

    传统的PBC组织学分期有Rubin分期、Scheuer分期和Ludwig分期,近年又有Nakanuma分期。虽然按新指南要求,PBC确诊不再完全依赖病理,但基于PBC的胆管损伤具有典型的形态学特点,特别对于AMA阴性PBC,肝活检确诊仍有重要意义,且肝组织病理更能准确反映PBC进展[12]。此外,PBC治疗效果评价、新药靶点的发现和选择,亦要依赖肝组织病理。现对不同PBC的组织学分期进行综述,为临床医师从事PBC诊治及相关研究提供参考。

    Rubin等[13]在1965年提出PBC早期的特点是汇管区炎细胞浸润和小叶间胆管损伤、小叶间胆管周围淋巴细胞和浆细胞的聚集,通常无明显胆汁淤积;中期出现胆管的增生和破坏,可见小叶中心和周围肝细胞胆汁淤积;晚期表现为肝硬化。

    Scheuer[14]在1967年将PBC分为4期:Ⅰ期的组织学改变为胆管损伤;Ⅱ期的组织学改变主要是胆管增生;Ⅲ期出现了桥接瘢痕,纤维隔;Ⅳ期为肝硬化。Hans Popper和Schaffner将Scheuer分期系统进行修订[15]:Ⅰ期为胆管明显损伤(汇管区炎症);Ⅱ期为细胆管增生(汇管区周围扩张和炎症);Ⅲ期为桥接瘢痕,纤维隔;Ⅳ期为肝硬化。

    1978年Ludwig提出了PBC分期系统[15],Ⅰ期组织学改变为汇管区炎症;Ⅱ期组织学改变为汇管区周围炎,即界面炎;Ⅲ期出现桥接坏死、纤维化;Ⅳ期为肝硬化。

    Nakanuma在2010年提出了一个新的分期系统[16],根据纤维化、胆管缺失、地衣红阳性颗粒沉积和坏死性炎症活动的严重程度进行分期和分级(表 1)。(1)对于纤维化,0分指的是几乎没有纤维化或纤维化局限于汇管区;1分指的是纤维化范围超出汇管区,偶有不完全纤维间隔;2分为桥接纤维化伴小叶紊乱;3分为肝硬化(广泛纤维化和再生结节)。(2)对于胆管缺失,0分指的是标本中的所有汇管区均可见小叶间胆管;1分和2分分别指的是在<1/3和1/3~ 2/3的汇管区有胆管缺失;3分指的是>2/3的汇管区有胆管缺失。(3)地衣红阳性颗粒是肝细胞溶酶体中的铜结合蛋白,它们的沉积反映了慢性胆盐淤积的程度,0分指的是汇管区周围肝细胞无沉积;1分指的是<1/3的汇管区周围肝细胞有沉积;3分为>2/3的汇管区或纤维间隔周围肝细胞有沉积;介于以上两种表现之间为2分。(4)在对每一项进行评分后,获得总分,根据总分进行分期。Ⅰ期(无进展):总分为0分;Ⅱ期(轻度进展):总分为1~3分;Ⅲ期(中度进展):总分为4~6分;Ⅳ期(重度进展):总分为7~9分。如果无法进行地衣红染色,则纤维化和胆管缺失评分的总和也适用,Ⅰ期(无进展):总分为0分;Ⅱ期(轻度进展):总分为1~2分;Ⅲ期(中度进展):总分为3~4分;Ⅳ期(重度进展):总分为5~6分。

    表  1  Nakanuma评分
    项目 病理表现
    纤维化评分
    0分 无纤维化,或纤维化局限于汇管区
    1分 汇管区纤维化伴汇管区周围纤维化或不完全纤维间隔
    2分 桥接纤维化伴小叶紊乱
    3分 肝硬化伴再生结节和广泛纤维化
    胆管缺失评分
    0分 无胆管缺失
    1分 <1/3的汇管区有胆管缺失
    2分 1/3~2/3的汇管区有胆管缺失
    3分 >2/3的汇管区有胆管缺失
    地衣红阳性颗粒的沉积评分
    0分 无地衣红阳性颗粒沉积
    1分 <1/3的汇管区周围肝细胞有颗粒沉积
    2分 1/3~2/3的汇管区周围肝细胞有颗粒沉积
    3分 >2/3的汇管区周围肝细胞有颗粒沉积
    下载: 导出CSV 
    | 显示表格

    坏死性炎症活动分级,分为胆管炎活动(cholangitis activity,CA)和肝炎活动(hepatitis activity,HA),这两种病变是PBC病理的两种重要改变,活动性胆管炎分级为CA 0~3,活动性肝炎分级为HA 0~3。CA0(无活动):无胆管炎,但可能存在轻度胆管上皮细胞损伤;CA1(轻度活动):可见一个受损的胆管表现为明显的慢性胆管炎(受损的胆管完全被轻度-中度的淋巴-浆细胞包围)。但是小叶间胆管被少量淋巴-浆细胞浸润或邻近淋巴细胞浸润的汇管区,则不被视为明显的慢性胆管炎;CA2(中度活动):超过两个胆管伴有明显的慢性胆管炎;CA3(重度活动):至少有一个受损的胆管表现为慢性非化脓性胆管炎,慢性非化脓性胆管炎表现为胆管上皮细胞受损,胆管完全被大量的淋巴-浆细胞浸润,受损的胆管部分或全部被上皮样肉芽肿包围(肉芽肿性胆管炎)。活动性肝炎(HA)分为4个等级,HA0(无活动):无界面肝炎,且无或最轻微的小叶性肝炎;HA1(轻度活动):指界面肝炎累及一个汇管区或纤维间隔周围连续10个肝细胞,且有轻度-中度小叶性肝炎;HA2(中度活动):界面肝炎累及两个以上汇管区或纤维间隔周围连续10个肝细胞,且有轻度-中度小叶性肝炎;HA3(重度活动):界面肝炎累及超过一半数量的汇管区周围连续20个肝细胞,且有中度小叶性肝炎或桥接或带状坏死。

    1950年“原发性胆汁性肝硬化”命名正式确定。随着对PBC诊断认识的深入,1965年Rubin及Hans Popper通过对大量PBC肝活检病例系统总结,阐述了PBC的形态学特点,尤为侧重PBC的形态学诊断及鉴别诊断,并对病变演变规律做了最初的总结。Scheuer系统,特别是Hans Popper修订版,较为清晰的提出4期分期方案,这一方案在应用和验证中获得很好的一致性。Ludwig明确界定各分期之间的分界点,包括Ⅰ期强调炎症限于汇管区间质,Ⅱ期强调了汇管区周围炎,即界面炎的重要性,Hans Popper修订版强调的是细胆管反应增生,Ludwig认为Ⅲ期出现桥接坏死或桥接纤维化,并强调了它们是PBC晚期(胆汁性肝硬化)的主要原因,这一点是继Hans Popper修订版之后的重大发现。

    传统分期体现了病理学家对PBC病变特点和进展规律的认识不断成熟的历程,尤其Ludwig分期系统,至今仍被美国肝病学会和欧洲肝病学会作为指南推荐,广泛应用于PBC相关的临床及科研,其在PBC病理学发展过程中具有不可取代的位置[17-18]

    虽然经典PBC分期方法各有自身优势,但随着这些分期系统在临床上被广泛应用,各自的局限性也渐渐显现。Rubin分期较为笼统不够精确,肝硬化阶段被清楚地描述,但肝硬化前各阶段之间的区别并不清楚[19]。Scheuer分期的缺点是各个分期阶段有大量的重叠,如Ⅳ期的患者肝脏可呈现Ⅰ或Ⅱ期的胆管改变。Popper和Schaffner与Scheuer主要不同的观点在于前者认为Ⅰ期的汇管区炎症不会累及肝实质,而Scheuer却有着相反的观点。在Ludwig的系统强调了胆管损伤不同阶段对于肝实质的影响,病变早期限于汇管区间质内,继而出现界面炎,最后形成胆汁性肝纤维化甚至胆汁性肝硬化。然而,非常重要的胆管损伤程度和胆汁淤积变化却未被评估在内。

    现阶段,由于临床诊断PBC的水平提高,PBC诊断和分期已不再完全依赖病理活检,病理技术需要被赋予新的历史任务和目标,如预测疾病进展、寻找新的/有效的治疗靶点和评估疗效的指标等,这样就需要涵盖更多敏感有效指标的新评价系统的出现,因此Nakanuma分期和分级系统应运而生。Nakanuma系统通过对肝纤维化、胆管缺失、地衣红阳性颗粒的沉积进行评分,再进行分期,并联合坏死性炎症活动的分级综合评判患者的严重程度与预后。

    与传统分期系统相比,Nakanuma分期系统与肝硬化相关症状的发展具有更好的相关性,有研究[20]报道坏死性炎症程度的分级与血清学指标如ALT、AST、ALP、GGT、TBil、DBil、IgM、IgG呈正相关。有研究[19]在同一组PBC病例10年随访中发现,以3种不同系统分期,患者出现肝硬化相关症状的比例不同。以Nakanuma系统划分,则Ⅰ~Ⅳ期患者随访10年分别有0、12.6%、40.6%和100%的病例进展至肝硬化;以Scheuer系统划分,则Ⅰ~Ⅲ期患者随访10年分别有7.5%、100%和40.3%的病例进展至肝硬化;以Ludwig系统划分,则Ⅰ~Ⅲ期患者随访10年分别有17.6%、4.6%和47.4%的病例进展至肝硬化。Nakanuma系统分期的肝硬化发生率随着分期的升高而升高。在随访中,对Nakanuma分期系统的组织学研究,观察到地衣红阳性颗粒的沉积与肝纤维化呈显著相关,胆管缺失评分为2或3分,特别是在地衣红阳性颗粒沉积评分为2~3分的患者中,肝硬化相关疾病的发展速度明显高于评分为0~1分的患者。因此与经典分期相比,Nakanuma分期系统更准确地预测了PBC患者的10年预后情况,尤其是肝硬化及其并发症。Nakanuma分期系统的Ⅰ期患者随访中并未出现肝硬化,Ⅱ期和Ⅲ期之间肝硬化的发生率有显著性差异。然而,在Scheuer系统和Ludwig系统中未观察到这种趋势。

    在取样过程中,典型的病变可能被遗漏在活检样本之外,增加了假阴性的几率,Nakanuma分期利用评分系统,更合理地最大程度地减少PBC肝组织学固有的采样误差,提供给临床医生更多客观信息,可常规应用于PBC组织学评估。目前,该分期系统广泛应用仍存在待研究的问题,例如,系统涉及评价项目繁琐,病理医生操作不易,一致性可能欠满意等。其次,新旧系统的对比研究论文比较少,需要更大队列验证,以更准确地验证这种新的Nakanuma分级和分期系统。旧系统在当下及未来仍具有举足轻重的作用,新旧系统可结合使用,从而为PBC患者的合理防治提供指导。

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