Bile

胆汁
  • 文章类型: Journal Article
    背景:作为四种最有价值的动物药物之一,FelUrsi,在中国叫熊丹(XD),具有清除热量的作用,平静肝脏,和明亮的眼睛。然而,由于XD的特殊来源和高昂的价格,其他动物胆汁通常以XD或与XD混合在市场上出售,严重影响其临床疗效和消费者权益。为了实现对XD的鉴别和掺假分析,UHPLC-QTOF-MSE和多变量统计分析用于探索XD和其他6只动物胆汁的差异。
    方法:XD,猪胆(朱丹,ZD),牛胆(牛丹,ND),兔胆囊(涂丹,TD),鸭胆(颜丹,YD),羊胆(杨丹,YND),和鸡胆(吉丹,JD)通过UHPLC-QTOF-MSE分析,和MS数据,结合多变量分析方法,被用来区分它们。同时,进一步探索了导致它们差异的潜在化学成分标记。
    结果:结果表明,XD和其他六只动物的胆汁可以明显区分开来,与27个离子与VIP>1.0。我们初步鉴定了XD和其他动物胆汁中10种不同的胆汁酸样成分,具有显着差异(p<0.01)和VIP>1.0,例如牛磺熊去氧胆酸,糖脱氧胆酸,和糖脱氧胆酸。
    结论:所开发的方法可以有效,快速地准确区分XD和其他六种动物的胆汁。根据获得的化学成分标记,有利于加强胆汁类药品的质量控制。
    BACKGROUND: As one of the four most valuable animal medicines, Fel Ursi, named Xiong Dan (XD) in China, has the effect of clearing heat, calming the liver, and brightening the eyes. However, due to the special source of XD and its high price, other animals\' bile is often sold as XD or mixed with XD on the market, seriously affecting its clinical efficacy and consumers\' rights and interests. In order to realize identification and adulteration analysis of XD, UHPLC-QTOF-MSE and multivariate statistical analysis were used to explore the differences in XD and six other animals\' bile.
    METHODS: XD, pig gall (Zhu Dan, ZD), cow gall (Niu Dan, ND), rabbit gallbladder (Tu Dan, TD), duck gall (Yan Dan, YD), sheep gall (Yang Dan, YND), and chicken gall (Ji Dan, JD) were analyzed by UHPLC-QTOF-MSE, and the MS data, combined with multivariate analysis methods, were used to distinguish between them. Meanwhile, the potential chemical composition markers that contribute to their differences were further explored.
    RESULTS: The results showed that XD and six other animals\' bile can be distinguished from each other obviously, with 27 ions with VIP > 1.0. We preliminarily identified 10 different bile acid-like components in XD and the other animals\' bile with significant differences (p < 0.01) and VIP > 1.0, such as tauroursodeoxycholic acid, Glycohyodeoxycholic acid, and Glycodeoxycholic acid.
    CONCLUSIONS: The developed method was efficient and rapid in accurately distinguishing between XD and six other animals\' bile. Based on the obtained chemical composition markers, it is beneficial to strengthen quality control for bile medicines.
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  • 文章类型: Journal Article
    背景:胰腺导管腺癌(PDAC)患者口腔改变,胃肠,和胰腺内微生物组与健康个体相比。然而,关于胆汁微生物组及其对PDAC无进展生存期的潜在影响的知识仍然有限.
    方法:PDAC患者(n=45),包括手术前后的20对配对,和良性对照(n=16)被纳入前瞻性研究。通过16S-rRNA基因测序揭示了总共81个胆汁的微生物群落特征。PDAC患者根据肿瘤标志物水平分为不同的组,疾病分期,手术前后,以及无进展生存期(PFS)进行进一步分析。利用随机森林算法建立疾病诊断模型。
    结果:PDAC患者拥有独特多样的胆汁微生物组(PCoA,加权Unifrac,p=0.038),根据关键微生物和微生物功能,微生物多样性的增加与菌群失调相关。Aliihoeflea是两组中表现出最显着变化的属(p<0.01)。发现长期PFS和短期PFS组之间胆汁微生物组的β多样性存在显着差异(PCoA,加权Unifrac,p=0.005)。在所有PDAC患者中,杆菌和放线菌被确定为与无进展生存期相关的两组之间的门改变。此外,我们确定了三个生物标志物作为随机森林模型的最合适的集合,这表明PDAC组发生疾病的可能性显着升高(p<0.0001)。受试者工作特征(ROC)曲线下面积达到80.8%,95%置信区间为55.0%至100%。由于胆汁样本的稀缺性,我们无法进行进一步的外部核查。
    结论:PDAC的特征是胆管微生物组改变。胆道菌群失调与所有PDAC的无进展生存期相关。这项研究揭示了PDAC中胆汁微生物组的改变,并成功开发了PDAC的诊断模型。
    BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) display an altered oral, gastrointestinal, and intra-pancreatic microbiome compared to healthy individuals. However, knowledge regarding the bile microbiome and its potential impact on progression-free survival in PDACs remains limited.
    METHODS: Patients with PDAC (n = 45), including 20 matched pairs before and after surgery, and benign controls (n = 16) were included prospectively. The characteristics of the microbiomes of the total 81 bile were revealed by 16  S-rRNA gene sequencing. PDAC patients were divided into distinct groups based on tumor marker levels, disease staging, before and after surgery, as well as progression free survival (PFS) for further analysis. Disease diagnostic model was formulated utilizing the random forest algorithm.
    RESULTS: PDAC patients harbor a unique and diverse bile microbiome (PCoA, weighted Unifrac, p = 0.038), and the increasing microbial diversity is correlated with dysbiosis according to key microbes and microbial functions. Aliihoeflea emerged as the genus displaying the most significant alteration among two groups (p < 0.01). Significant differences were found in beta diversity of the bile microbiome between long-term PFS and short-term PFS groups (PCoA, weighted Unifrac, p = 0.005). Bacillota and Actinomycetota were identified as altered phylum between two groups associated with progression-free survival in all PDAC patients. Additionally, we identified three biomarkers as the most suitable set for the random forest model, which indicated a significantly elevated likelihood of disease occurrence in the PDAC group (p < 0.0001). The area under the receiver operating characteristic (ROC) curve reached 80.8% with a 95% confidence interval ranging from 55.0 to 100%. Due to the scarcity of bile samples, we were unable to conduct further external verification.
    CONCLUSIONS: PDAC is characterized by an altered microbiome of bile ducts. Biliary dysbiosis is linked with progression-free survival in all PDACs. This study revealed the alteration of the bile microbiome in PDACs and successfully developed a diagnostic model for PDAC.
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  • 文章类型: Case Reports
    Bilothorax定义为胸膜腔中胆汁的存在。这是一种罕见的情况,胸膜液与血清胆红素比值>1时确诊。
    PubMed,Embase,谷歌学者,使用预定的布尔参数搜索和CINAHL数据库。根据PRISMA指南进行系统文献综述。回顾性研究,案例系列,病例报告,包括会议摘要。合并报告有胸腔积液分析的患者,以进行流体参数数据分析。
    在通过纳入标准确定的838篇文章中,删除了105篇重复文章,732篇文章用摘要进行了筛选,对285例进行了全面审查。在这之后,123项研究有资格进行进一步的详细审查,其中,将115个数据汇总用于数据分析。平均胸水和血清胆红素水平为72mg/dL和61mg/dL,分别,平均胸水与血清胆红素的比值为3.47。在大多数情况下,据报道,胆胸是肝胆手术或手术的亚急性或远端并发症,胸部或腹部的外伤是第二大常见原因。管状胸腔造口术是主要的治疗方式(73.83%),然后是连续胸腔穿刺术.52例患者(51.30%)患有相关的支气管胸膜瘘。死亡率相当高,18/115(15.65%)报告死亡。大多数死亡患者患有晚期肝胆管癌,并死于与胆胸无关的并发症。
    在手术操作肝胆结构或胸部外伤后出现胸腔积液的患者应怀疑有Bilothorax。此评论已在CRD42023438426注册。
    UNASSIGNED: Bilothorax is defined as the presence of bile in the pleural space. It is a rare condition, and diagnosis is confirmed with a pleural fluid-to-serum bilirubin ratio of >1.
    UNASSIGNED: The PubMed, Embase, Google Scholar, and CINAHL databases were searched using predetermined Boolean parameters. The systematic literature review was done per PRISMA guidelines. Retrospective studies, case series, case reports, and conference abstracts were included. The patients with reported pleural fluid analyses were pooled for fluid parameter data analysis.
    UNASSIGNED: Of 838 articles identified through the inclusion criteria and removing 105 duplicates, 732 articles were screened with abstracts, and 285 were screened for full article review. After this, 123 studies qualified for further detailed review, and of these, 115 were pooled for data analysis. The mean pleural fluid and serum bilirubin levels were 72 mg/dL and 61 mg/dL, respectively, with a mean pleural fluid-to-serum bilirubin ratio of 3.47. In most cases, the bilothorax was reported as a subacute or remote complication of hepatobiliary surgery or procedure, and traumatic injury to the chest or abdomen was the second most common cause. Tube thoracostomy was the main treatment modality (73.83%), followed by serial thoracentesis. Fifty-two patients (51.30%) had associated bronchopleural fistulas. The mortality was considerable, with 18/115 (15.65%) reported death. Most of the patients with mortality had advanced hepatobiliary cancer and were noted to die of complications not related to bilothorax.
    UNASSIGNED: Bilothorax should be suspected in patients presenting with pleural effusion following surgical manipulation of hepatobiliary structures or a traumatic injury to the chest. This review is registered with CRD42023438426.
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  • 文章类型: Journal Article
    肝移植术后胆漏(BL)的治疗没有标准的管理方案。这项研究的目的是描述小儿LT术后BL的治疗选择。
    方法:回顾性分析(2010年1月至2023年3月)。
    方法:术前数据,诊断时的状态,和术后结果。四组:观察(n=9),经皮肝穿刺胆管造影(PTC,n=38),ERCP(2),和手术(n=27)。
    结果:9131例小儿肝移植(859例LDLT和72例DDT);78例(8.3%)患者患有BL,所有在LDLT。诊断时的中位(IQR)腹膜胆红素(PB)水平和液体与血清胆红素之比(FSBR)为14.40mg/dL(8.5-29),和10.7(4.1-23.7)。需要手术治疗的患者较早接受了手术,中位数为14天(IQR:7-19),PTC为22天(IQR:15-27,p=0.002)。观察组PB和FSBR均显著降低。在11个案例中,保守管理在平均35天的时间内解决了BL,38例患者接受PTC的中位时间为22天(15-27)。27例(34.6%)患者作为BL的初始治疗再次手术,中位时间为17天(1-108天);25例(33%)患者出现胆道狭窄,5(18.5%)术后,PTC后20(52.6%)(p=0.01)。
    结论:观察到的BL患者的PB和FSBR水平明显低于接受PTC或手术的患者。接受PTC治疗的患者在随访期间胆道狭窄的发生率更高。
    There are no standard management protocols for the treatment of bile leak (BL) after liver transplantation. The objective of this study is to describe treatment options for BL after pediatric LT.
    METHODS: Retrospective analysis (January 2010-March 2023).
    METHODS: preoperative data, status at diagnosis, and postoperative outcome. Four groups: observation (n = 9), percutaneous transhepatic cholangiography (PTC, n = 38), ERCP (2), and surgery (n = 27).
    RESULTS: Nine hundred and thirty-one pediatric liver transplantation (859 LDLT and 72 DDT); 78 (8.3%) patients had BL, all in LDLT. The median (IQR) peritoneal bilirubin (PB) level and fluid-to-serum bilirubin ratio (FSBR) at diagnosis was 14.40 mg/dL (8.5-29), and 10.7 (4.1-23.7). Patients who required surgery for treatment underwent the procedure earlier, at a median of 14 days (IQR: 7-19) versus 22 days for PTC (IQR: 15-27, p = 0.002). PB and FSBR were significantly lower in the observation group. In 11 cases, conservative management had resolution of the BL in an average time of 35 days, and 38 patients underwent PTC in a median time of 22 days (15-27). Twenty-seven (34.6%) patients were reoperated as initial treatment for BL in a median time of 17 days (1-108 days); 25 (33%) patients evolved with biliary stricture, 5 (18.5%) after surgery, and 20 (52.6%) after PTC (p = 0.01).
    CONCLUSIONS: Patients with BL who were observed presented significantly lower levels of PB and FSBR versus those who underwent PTC or surgery. Patients treated with PTC presented higher rates of biliary stricture during the follow-up.
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  • 文章类型: Journal Article
    使用下一代测序(NGS)鉴定抗癌疗法对于治疗胆管癌是必要的。当从储存过夜的胆汁中获得细胞块(CB)时,可以容易地进行NGS。我们比较了来自相同胆管癌病例的配对CB和手术切除标本(SRS)的NGS结果。在2018年至2023年前瞻性收集的64例胆汁CBs中,对3例胆管癌进行了NGS,可与SRS结果进行比较。DNA和RNA读数的中位数为95,077,806[CB]vs.93,161,788[SRS]和22,101,328[CB]vs.24,806,180[SRS],分别。我们评估了588个基因,发现几乎所有的遗传变异都归因于单核苷酸变异,插入/删除,和多核苷酸变体。CB中发现的SRS变体的覆盖率为97.9-99.2%,CB基因对SRS基因的覆盖率为99.6-99.7%。CB的NGS结果完全涵盖了配对SRS样品中观察到的变体和遗传改变。由于胆汁CB在综合医院很容易制备,我们的结果表明,胆汁CB作为一种基于NGS的胆管癌评估新方法的潜在用途.
    The identification of anticancer therapies using next-generation sequencing (NGS) is necessary for the treatment of cholangiocarcinoma. NGS can be easily performed when cell blocks (CB) are obtained from bile stored overnight. We compared NGS results of paired CB and surgically resected specimens (SRS) from the same cholangiocarcinoma cases. Of the prospectively collected 64 bile CBs from 2018 to 2023, NGS was performed for three cases of cholangiocarcinoma that could be compared with the SRS results. The median numbers of DNA and RNA reads were 95,077,806 [CB] vs. 93,161,788 [SRS] and 22,101,328 [CB] vs. 24,806,180 [SRS], respectively. We evaluated 588 genes and found that almost all genetic alterations were attributed to single-nucleotide variants, insertions/deletions, and multi-nucleotide variants. The coverage rate of variants in SRS by those found in CB was 97.9-99.2%, and the coverage rate of SRS genes by CB genes was 99.6-99.7%. The NGS results of CB fully covered the variants and genetic alterations observed in paired SRS samples. As bile CB is easy to prepare in general hospitals, our results suggest the potential use of bile CB as a novel method for NGS-based evaluation of cholangiocarcinoma.
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  • 文章类型: Journal Article
    暂无摘要。
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  • 文章类型: Journal Article
    梗阻性黄疸(OJ)的诊断是一项挑战,通常在资源不足的情况下尤其如此。在马拉维和撒哈拉以南非洲,关于阻塞性黄疸患者的病因和预后的数据很少。这项研究的目的是确定病因,临床表现,以及马拉维接受OJ治疗的患者的短期治疗结果。
    对2012年至2022年临床诊断为OJ的所有患者的病例记录进行了回顾。我们回顾了临床表现,实验室发现,管理,术中和术后并发症,和患者结果。将数据输入到Excel电子表格中并使用SPSS版本25进行分析。
    在26,796名患者中,5339(19.9%)为非外伤腹部症状,其中164例(手术入院的0.6%和腹部症状的3%)为阻塞性黄疸.年龄从16岁到89岁不等。女性占人口的45(58.4%)。最常见的主诉是黄疸,然后是腹痛和腹胀。出现时症状的平均持续时间为8.5周。最常见的成像方式是腹部超声50(65%)。26例(33.8%)出院,诊断为病因不明的阻塞性黄疸。最常见的诊断是胰腺癌20(26.0%),其次是胆总管11(14.3%)。50岁以下的患者与50岁以上的患者患癌症的可能性相同。
    对于所有出现梗阻性黄疸的成年患者,高度怀疑是很重要的,因为50岁以下的患者与老年患者有相似的恶性肿瘤风险。
    UNASSIGNED: The diagnosis of obstructive jaundice (OJ) is a challenge and is often made late especialy in low-resource settings. There is a paucity of data on the aetiology and prognosis of patients with obstructive jaundice in Malawi and Sub-Saharan Africa. The objective of this study was to determine the aetiology, clinical presentations, and short-term treatment outcomes of patients managed for OJ in Malawi.
    UNASSIGNED: A review of case notes of all patients admitted with a clinical diagnosis of OJ from 2012 to 2022 was done. We reviewed the clinical presentation, laboratory findings, management, intra and post-operative complications, and patient outcomes. Data was entered into an Excel spreadsheet and analysed using SPSS version 25.
    UNASSIGNED: Of 26,796 patient admissions, 5339 (19.9%) were for non-trauma abdominal symptoms, of which 164 (0.6% of surgical admissions and 3% of abdominal symptoms) were for obstructive jaundice. Ages varied from 16 to 89 years. Females were 45 (58.4 %) of the population. The commonest presenting complaint was jaundice followed by abdominal pain and distention. The mean duration of symptoms at presentation was 8.5 weeks. The most frequent imaging modality was abdominal ultrasound 50(65 %). Twenty-six patients (33.8 %) were discharged with a diagnosis of obstructive jaundice of undetermined pathogenesis. The commonest diagnosis was pancreatic cancer 20(26.0 %) followed by Choledocholithiasis11(14.3 %). Patients younger than 50 years had the same likelihood of presenting with cancer as those older than 50 years.
    UNASSIGNED: It is important to have a high index of suspicion in all adult patients presenting with obstructive jaundice as patients younger than 50 years have a similar risk of malignancy as older patients.
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  • 文章类型: Journal Article
    胆道菌群失调与胆囊癌(GBC)有关。我们旨在寻找在GBC患者中特异性检测到的胆道细菌。我们使用基于16SrRNA的宏基因组分析来阐明30个GBC和30个胆结石相关的慢性胆囊炎患者的胆道微生物群。五个属的相对丰度,链球菌,肠球菌,Halomonas,大肠埃希氏菌和枯草杆菌与GBC显著相关。15种,7在GBC中检测到显著较高,硬化链球菌,星座链球菌,中间链球菌,鲍德尼放线菌,放线菌以色列,放线菌,和大肠杆菌为生物安全2级感染细菌;其他8种为生物安全1级细菌。这些细菌可能与GBC的发病机理有关。
    Biliary dysbiosis is associated with gallbladder cancer (GBC). We aimed to look for biliary bacteria specifically detected in GBC patients. We used 16S rRNA-based metagenomic analysis to elucidate biliary microbiota in 30 GBC and 30 gallstones-associated chronic cholecystitis patients. Relative abundance of five genera, Streptococcus, Enterococcus, Halomonas, Escherichia and Caulobacter was significantly associated with GBC. Of 15-species, 7 were detected significantly higher in GBC, Streptococcus anginosus, Streptococcus constellatus, Streptococcus intermedius, Actinomyces bowdenii, Actinomyces israelii, Actinomyces gerencseriae, and Escherichia fergusonii were biosafety level-2 infectious bacteria; other 8 species were biosafety level-1 bacteria. These bacterial species may be involved in pathogenesis of GBC.
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  • 文章类型: Journal Article
    背景:在人类护理下的非人类灵长类动物中的PlatynoSomiasis会导致胆管和肝脏的慢性疾病,最初表现为非特异性体征,并最终导致动物死亡。诊断这种疾病是一个挑战,当怀疑时,超声波检查可能是一个很好的工具。
    方法:本研究描述了57例疑似感染桔梗的小鼠的超声检查结果。,相关的肝胆变化,和解剖病理学发现证实了颈髓病的发生。
    结果:在六只猴子中(一只C.aurita,两个C.Jacchus,和三个Callithrixsp。),在宏观上(胆囊中存在成年吸虫)和显微镜下(成人,幼虫,和组织学检查中的卵和胆汁和粪便中的卵)。这些发现与死前评估中的肝胆变化以及暗示寄生虫结构的图像相符。
    结论:超声检查证明其在临床常规中用于研究这种寄生虫病。
    BACKGROUND: Platynosomiasis in non-human primates kept under human care causes chronic disease of the bile ducts and liver, which initially presents with nonspecific signs and can culminate in the death of the animal. Diagnosing this disease is a challenge, and an ultrasound examination can be an excellent tool when it is suspected.
    METHODS: This study describes the ultrasound findings from 57 marmosets with suspected infection by Platynosomum sp., the correlated hepatobiliary changes, and the anatomopathological findings that confirmed the occurrence of platynosomiasis.
    RESULTS: In six marmosets (one C. aurita, two C. jacchus, and three Callithrix sp.), Platynosomum infection was confirmed macroscopically (presence of adult trematodes in the gallbladder) and microscopically (adults, larvae, and eggs in histological examinations and eggs in bile and feces). These findings were compatible with the hepatobiliary changes and with images suggestive of parasitic structures in ante-mortem assessments.
    CONCLUSIONS: Ultrasound examination demonstrated its usefulness within the clinical routine for investigating this parasitosis.
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  • 文章类型: Journal Article
    食用含有二环amanitin八肽的错误识别的觅食蘑菇是全球公共卫生和兽医问题,被认为是由于急性肝功能衰竭(ALF)导致的最致命的意外人类和犬类食物摄入之一。从胆囊中明确清除积聚的富含amatoxin的胆汁后,可以实现晚期ALF的逆转和临床完全恢复。定量吸入胆汁中amanitin含量的准确方法是,因此,迫切需要。在我们先前的工作基础上,验证了一种检测和量化肝尸检组织中amanitin的方法,我们开发了一种准确的方法来测量抽吸胆囊胆汁中的α-和β-amanitin,以评估这种急诊手术作为中毒患者临床治疗的有效性。优化了固相萃取(SPE)程序,然后基于超高效液相色谱与质谱联用(UHPLC-MS)进行检测。通过UHPLC-MS/MS(三重四极杆MS)和UHPLC-ToF-MS(飞行时间MS)的验证,将低分辨率质谱(LRMS)与高分辨率(HRMS)进行了比较。两种方法均能够检测胆汁中的阿莫毒素,检出限和定量范围为2.71至3.46µg。kg-1和8.36-9.03µg。kg-1用于α-amanitin和,0.32-1.69µg。kg-1和0.55-5.62µg。kg-1为β-amanitin,分别。通过线性评估完成验证,特异性,鲁棒性,recovery,和精确度遵循ICH指南和CIR808/2021。最终将经过验证的方法应用于从越南接受胆囊引流程序的4名阿马毒素中毒患者摄入后48-96小时获得的胆汁样品,加拿大,和加州。amatoxin蘑菇中毒患者的胆囊胆汁含有显著的amanitin含量,即使在摄入后几天吸气,从而证实肠肝循环在amatoxin肝毒性中的重要作用。这项工作代表了抗菌肽中毒的高而独特的分析能力,可以有效地应对这种致命的健康问题。
    Consumption of misidentified foraged mushrooms containing bicyclic amanitin octapeptides is a worldwide public health and veterinary problem, being considered one of the deadliest accidental human and canine food ingestion due to acute liver failure (ALF). Reversal of advanced ALF and complete clinical recovery can be achieved following definitive removal of accumulated amatoxin laden bile from the gallbladder. An accurate means of quantifying amanitin content in aspirated bile is, therefore, urgently needed. Building on our prior work validating a method to detect and quantify amanitin in hepatic autopsy tissue, the development of an accurate method of measuring α- and β-amanitin in aspirated gallbladder bile was performed to evaluate the efficiency of this emergency procedure applied as a clinical treatment for intoxicated patients. A solid-phase extraction (SPE) procedure was optimized followed by detection based on ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Low resolution mass spectrometry (LRMS) was compared with high resolution (HRMS) by the validation of UHPLC-MS/MS (triple quadrupole MS) and UHPLC-ToF-MS (time-of-flight MS). Both methods were able to detect amatoxins in bile with limits of detection and quantification ranging from 2.71 to 3.46 µg.kg-1, and 8.36-9.03 µg.kg-1 for α-amanitin and, 0.32-1.69 µg.kg-1 and 0.55-5.62 µg.kg-1 for β-amanitin, respectively. Validation was completed with the evaluation of linearity, specificity, robustness, recovery, and precision following the ICH guidelines and CIR 808/2021. The validated methods were finally applied to bile samples obtained 48-96 hours + post-ingestion from 4 amatoxin poisoning patients who underwent gallbladder drainage procedures in Vietnam, Canada, and California. Gallbladder bile from patients with amatoxin mushroom poisoning contained significant amanitin content, even when aspirated several days post-ingestion, thus confirming the important role of enterohepatic circulation in amatoxin hepatotoxicity. This work represents a high and unique analytical throughput in amanitin poisoning allowing to efficiently respond to this fatal health problem.
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