Ursodeoxycholic Acid

熊去氧胆酸
  • 文章类型: Journal Article
    已经建立了肠道微生物与心血管疾病(CVD)之间的关联,但是潜在的机制在很大程度上仍然未知。
    我们对男性代谢综合征(METSIM)基于人群的10,194名芬兰男性(年龄=57.65±7.12岁)队列中获得的横断面数据进行了二次分析。我们测试了循环肠道微生物衍生代谢物的水平作为CVD的预测因子,缺血性脑血管意外(CVA),心肌梗死(MI)。使用Kaplan-Meier方法估计参与者从首次门诊就诊到出现不良结局的时间。使用Cox比例风险模型评估代谢物水平与结果之间的关联。
    在200个月的中位随访期间,979名参与者经历了CVD,397经验丰富的CVA,和548经验丰富的MI。在对传统风险因素进行调整并校正多重比较后,琥珀酸的血浆水平较高[四分位数4vs.四分位数1;调整后的危险比,aHR=1.30,(置信区间(CI),1.10-1.53)p=0.0003,调整后p=0.01]与CVD风险显著相关。熊去氧胆酸(UDCA)的高血浆水平(四分位数3vs.四分位数1);[aHR=1.68,(CI,1.26-2.2);p=0.0003,调整。p=0.01]与较高的CVA风险相关。此外,作为连续变量,琥珀酸盐与CVD风险降低10%相关[aHR=0.9;(CI,0.84~0.97);p=0.008],MI风险降低15%[aHR=0.85,(CI,0.77~0.93);p=0.0007].
    肠道微生物衍生代谢物,琥珀酸盐,熊去氧胆酸与CVD有关,MI,还有CVA,分别。调节肠道微生物可以代表用于调节CVD和CVA的潜在治疗靶标。
    UNASSIGNED: An association between gut microbes and cardiovascular disease (CVD) has been established, but the underlying mechanisms remain largely unknown.
    UNASSIGNED: We conducted a secondary analysis of the cross-sectional data obtained from the Metabolic Syndrome in Men (METSIM) population-based cohort of 10,194 Finnish men (age = 57.65 ± 7.12 years). We tested the levels of circulating gut microbe-derived metabolites as predictors of CVD, ischemic cerebrovascular accident (CVA), and myocardial infarction (MI). The Kaplan-Meier method was used to estimate the time from the participants\' first outpatient clinic visit to the occurrence of adverse outcomes. The associations between metabolite levels and the outcomes were assessed using Cox proportional hazard models.
    UNASSIGNED: During a median follow-up period of 200 months, 979 participants experienced CVD, 397 experienced CVA, and 548 experienced MI. After adjusting for traditional risk factors and correcting for multiple comparisons, higher plasma levels of succinate [quartile 4 vs. quartile 1; adjusted hazard ratio, aHR = 1.30, (confidence interval (CI), 1.10-1.53) p = 0.0003, adjusted p = 0.01] were significantly associated with the risk of CVD. High plasma levels of ursodeoxycholic acid (UDCA) (quartile 3 vs. quartile 1); [aHR = 1.68, (CI, 1.26-2.2); p = 0.0003, adj. p = 0.01] were associated with a higher risk of CVA. Furthermore, as a continuous variable, succinate was associated with a 10% decrease in the risk of CVD [aHR = 0.9; (CI, 0.84-0.97); p = 0.008] and a 15% decrease in the risk of MI [aHR = 0.85, (CI, 0.77-0.93); p = 0.0007].
    UNASSIGNED: Gut microbe-derived metabolites, succinate, and ursodeoxycholic acid were associated with CVD, MI, and CVA, respectively. Regulating the gut microbes may represent a potential therapeutic target for modulating CVD and CVA.
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  • 文章类型: Journal Article
    背景:胆石症是减肥手术后更常见的并发症之一。这可能与这段时间快速减肥有关,虽然减肥手术后胆结石形成的确切机制尚未完全阐明。
    方法:本文献综述侧重于风险因素,减肥手术后的预防选择和肠道菌群对胆囊结石发展的影响。
    结果:减肥手术后胆石症发展的潜在危险因素可能是肠道微生物群和胆汁酸组成的变化。胆汁酸之一-熊去氧胆酸-被认为降低粘蛋白的浓度,因此有助于减少胆石症患者胆固醇晶体的形成。此外,它降低了减肥手术后无症状和有症状胆结石的风险。减重手术后发生胆结石的患者的gnavusRuminococus的丰度较高,而未发生胆石症的患者的乳杆菌科和肠杆菌科的丰度较高。
    结论:减肥手术后胆囊结石形成的确切机制尚未阐明。研究表明,肠道微生物群和胆汁酸可能在其中发挥重要作用。
    BACKGROUND: Cholelithiasis is one of the more common complications following bariatric surgery. This may be related to the rapid weight loss during this period, although the exact mechanism of gallstone formation after bariatric surgery has not been fully elucidated.
    METHODS: The present literature review focuses on risk factors, prevention options and the impact of the gut microbiota on the development of gallbladder stones after bariatric surgery.
    RESULTS: A potential risk factor for the development of cholelithiasis after bariatric surgery may be changes in the composition of the intestinal microbiota and bile acids. One of the bile acids-ursodeoxycholic acid-is considered to reduce the concentration of mucin proteins and thus contribute to reducing the formation of cholesterol crystals in patients with cholelithiasis. Additionally, it reduces the risk of both asymptomatic and symptomatic gallstones after bariatric surgery. Patients who developed gallstones after bariatric surgery had a higher abundance of Ruminococcus gnavus and those who did not develop cholelithiasis had a higher abundance of Lactobacillaceae and Enterobacteriaceae.
    CONCLUSIONS: The exact mechanism of gallstone formation after bariatric surgery has not yet been clarified. Research suggests that the intestinal microbiota and bile acids may have an important role in this.
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  • 文章类型: Journal Article
    背景:原发性胆汁性胆管炎(PBC)的基础治疗是熊去氧胆酸(UDCA)。但是许多患者表现出不完全的反应,导致疾病进展。GLOBE和UK-PBC评分等风险预测模型有望对患者进行分层和管理。我们旨在独立评估这些风险评分对美国前瞻性队列中UDCA反应的预测准确性。方法:我们在美国肝脏中心进行了一项前瞻性队列研究,在一年的随访中监测UDCA治疗的PBC患者。我们评估了GLOBE和UK-PBC评分对UDCA治疗反应的预测疗效,将它们与巴黎II标准进行比较。使用单变量和多变量分析评估疗效,然后通过受试者工作特征(ROC)曲线分析进行预后性能评估。结果:我们评估了136例接受UDCA治疗的PBC患者。根据巴黎二号标准,患者被分为UDCA完全缓解和无缓解组.GLOBE评分确定无反应率为18%(p=0.205),与巴黎II标准的20%(p=0.014)相比。多变量分析,根据年龄和生化指标进行调整,结果显示,GLOBE和UK-PBC评分均与治疗反应密切相关(p<0.001)。GLOBE评分的ROC曲线下面积为0.87(95%CI0.83-0.95),UK-PBC风险评分为0.94(95%CI0.86-0.99)。结论:我们的研究表明,GLOBE和UK-PBC评分可有效预测PBC患者的UDCA治疗反应。早期识别有不完全反应风险的患者可以改善治疗策略,并识别可能需要二线治疗的患者。
    Background: The cornerstone treatment for primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA), but many patients exhibit an incomplete response, leading to disease progression. Risk prediction models like the GLOBE and UK-PBC scores hold promise for patient stratification and management. We aimed to independently assess the predictive accuracy of these risk scores for UDCA response in a prospective U.S. cohort. Methods: We conducted a prospective cohort study at a U.S. liver center, monitoring UDCA-treated PBC patients over a one-year follow-up. We evaluated the predictive efficacy of the GLOBE and UK-PBC scores for UDCA treatment response, comparing them to the Paris II criteria. Efficacy was assessed using univariate and multivariate analyses, followed by prognostic performance evaluation via receiver operating characteristic (ROC) curve analysis. Results: We evaluated 136 PBC patients undergoing UDCA therapy. Based on the Paris II criteria, patients were categorized into UDCA full-response and non-response groups. The GLOBE score identified a non-responder rate of 18% (p = 0.205), compared to 20% (p = 0.014) with the Paris II criteria. Multivariate analysis, adjusted for age and biochemical markers, showed that both the GLOBE and UK-PBC scores were strongly associated with treatment response (p < 0.001). The area under the ROC curve was 0.87 (95% CI 0.83-0.95) for the GLOBE score and 0.94 (95% CI 0.86-0.99) for the UK-PBC risk score. Conclusions: Our study demonstrates that GLOBE and UK-PBC scores effectively predict UDCA treatment response in PBC patients. The early identification of patients at risk of an incomplete response could improve treatment strategies and identify patients who may need second-line therapies.
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  • 文章类型: Journal Article
    Seladelpar(MBX-8025)是在3期和扩展试验中每日一次给予的高度特异性PPAR-δ激动剂,用于原发性胆汁性胆管炎(PBC)患者。
    这篇综述提供了PBC当前治疗方案的背景,并总结了有关seladelpar在这些治疗中的安全性和有效性的临床试验数据。
    临床试验结果证明了Seladelpar用于PBC的安全性和耐受性,包括肝硬化患者。主要复合终点(ALP<1.67倍ULN,从基线下降≥15%,在接受seladelpar治疗的患者中,有61.7%和接受安慰剂治疗的患者中,有20%的患者符合TB≤ULN)(p<0.001)。此外,瘙痒-PBC的主要且通常难以治疗的症状-通过seladelpar治疗得到改善,总体生活质量测量也是如此。同样观察到炎症标志物的改善。因此,这些生化和临床发现代表了PBC治疗中具有里程碑意义的发展,并为PBC提供了治疗选择。
    UNASSIGNED: Seladelpar (MBX-8025) is a once-daily administered highly specific PPAR-δ agonist in Phase 3 and extension trials for use in patients with primary biliary cholangitis (PBC).
    UNASSIGNED: This review provides background on current treatment options for PBC, and summarizes clinical trial data regarding the safety and effectiveness of seladelpar within the context of these treatments.
    UNASSIGNED: Clinical trials results demonstrate the safety and tolerability of seladelpar use for PBC, including in patients with cirrhosis. The primary composite endpoint (ALP <1.67 times ULN, decrease ≥ 15% from baseline, and TB ≤ULN) was met in 61.7% of the patients treated with seladelpar and in 20% receiving placebo (p < 0.001). Moreover, pruritus - a cardinal and often intractable symptom of PBC - was improved with seladelpar treatment, as were overall quality of life measurements. Improvements in markers of inflammation were likewise observed. These biochemical and clinical findings therefore represent landmark developments in PBC treatment and offer a therapeutic option for PBC.
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  • 文章类型: Journal Article
    生物膜是一种复杂的微生物结构,可促进持续感染的进展,特别是在医院设置通过留置医疗设备。常规抗生素通常是对生物膜的无效治疗;因此,研究或设计能够成功减少和根除生物膜相关感染的非抗生素抗生物膜化合物至关重要。这项研究试图重新使用抗高血压和抗血脂药物类别的慢性疾病药物,包括坎地沙坦酯(CC)和熊去氧胆酸(UDCA),分别,用作抗两种感染性病原体金黄色葡萄球菌和粪肠球菌的抗生物膜剂。使用结晶紫(CV)染色测定来评估药物的抗生物膜活性。在用不同浓度的CC和UDCA处理后,进行实时聚合酶链反应(RT-PCR)以确定生物膜相关基因(金黄色葡萄球菌中的icaA和icaR以及粪肠球菌中的fsrC和gelE)的转录水平。我们发现,浓度大于1.5µg/ml的CC显着(p<0.005)抑制了两种细菌分离物的生物膜形成,浓度大于50µg/ml的UDCA显着(p<0.005)抑制了两种细菌分离物的生物膜形成。有趣的是,在浓度低于人类每日药物剂量的两个细菌分离株中,生物膜相关基因的mRNA表达水平降低.
    A biofilm is a complex microbial structure that promotes the progression of persistent infections, particularly in nosocomial settings via indwelling medical devices. Conventional antibiotics are often ineffective treatments for biofilms; hence, it is crucial to investigate or design non-antibiotic antibiofilm compounds that can successfully reduce and eradicate biofilm-related infections. This study was an attempt to repurpose chronic disease medications of the antihypertensive and antilipidemic drug classes, including candesartan cilexetil (CC) and ursodeoxycholic acid (UDCA), respectively, to be used as antibiofilm agents against the two infectious pathogens Staphylococcus aureus and Enterococcus faecalis. Crystal violet (CV) staining assay was used to evaluate the antibiofilm activity of the drugs. Real-time polymerase chain reaction (RT-PCR) was performed to determine the transcription levels of the biofilm-related genes (icaA and icaR in S. aureus and fsrC and gelE in E. faecalis) following treatment with different concentrations of CC and UDCA. we found that a concentration of greater than 1.5 µg/ml of CC significantly (p < 0.005) inhibited the biofilm formation of both bacterial isolates, and a concentration of greater than 50 µg/ml of UDCA significantly (p < 0.005) inhibited the biofilm formation of both bacterial isolates. Interestingly, the mRNA expression levels of biofilm-related genes were decreased in the two bacterial isolates at concentrations that were lower than the human pharmaceutical daily doses.
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  • 文章类型: Journal Article
    背景:胆汁酸(BA)是类固醇衍生的分子,在消化中具有重要作用,维持宿主的新陈代谢,和免疫调节。主BA由主机合成,而次级BA是由肠道微生物组通过前者的转化产生的。对次级BA的微生物生产的调节还没有很好的理解,特别是7-脱羟基BA的生产,它们是宿主BA受体最有效的激动剂。胆酸(CA)的7-脱羟基作用已得到很好的建立,并且与负责该过程的胆汁酸诱导型(bai)操纵子的表达有关。然而,对于其他宿主衍生的BA,几乎没有7-脱羟基的报道(例如,鹅去氧胆酸,CDCA或熊去氧胆酸,UDCA)。
    结果:这里,我们证明,当CA存在时,人分离梭菌scindens诱导CDCA和UDCA的7-脱羟基作用,表明CA依赖性转录调节是这些主要BA的大量7-脱羟基作用所必需的。这得到单独的UDCA不促进bai基因表达的发现的支持。CDCA上调bai基因的表达,但当CA存在时,表达更高。相比之下,鼠分离株Extibactermuris表现出明显的反应;CA没有诱导主要BAs的显着7-脱羟基化,而BA7-脱羟基作用在体外添加无菌小鼠盲肠含量后得到促进。然而,发现E.muris在体内7-去羟基化。
    结论:菌株之间不同的表达反应表明bai基因受到不同的调控。CA在C.scindens菌株中促进bai操纵子基因表达和7-脱羟基活性。相反,仅在添加盲肠内容物后,E.muris的体外活性才得到促进,并且该分离株不会响应CA改变bai基因的表达。辅助基因baiJ仅在C.scindensATCC35704菌株中上调,暗示分离株之间的机械差异。有趣的是,人来源的C.scindens菌株也能够在有限的程度上对鼠胆汁酸(胞嘧啶酸)进行7-脱羟基。这项研究显示了由于CA的存在而在体外产生的新的7-脱羟基活性,并暗示了跨细菌物种的不同bai基因表达。
    BACKGROUND: Bile acids (BAs) are steroid-derived molecules with important roles in digestion, the maintenance of host metabolism, and immunomodulation. Primary BAs are synthesized by the host, while secondary BAs are produced by the gut microbiome through transformation of the former. The regulation of microbial production of secondary BAs is not well understood, particularly the production of 7-dehydroxylated BAs, which are the most potent agonists for host BA receptors. The 7-dehydroxylation of cholic acid (CA) is well established and is linked to the expression of a bile acid-inducible (bai) operon responsible for this process. However, little to no 7-dehydroxylation has been reported for other host-derived BAs (e.g., chenodeoxycholic acid, CDCA or ursodeoxycholic acid, UDCA).
    RESULTS: Here, we demonstrate that the 7-dehydroxylation of CDCA and UDCA by the human isolate Clostridium scindens is induced when CA is present, suggesting that CA-dependent transcriptional regulation is required for substantial 7-dehydroxylation of these primary BAs. This is supported by the finding that UDCA alone does not promote expression of bai genes. CDCA upregulates expression of the bai genes but the expression is greater when CA is present. In contrast, the murine isolate Extibacter muris exhibits a distinct response; CA did not induce significant 7-dehydroxylation of primary BAs, whereas BA 7-dehydroxylation was promoted upon addition of germ-free mouse cecal content in vitro. However, E. muris was found to 7-dehydroxylate in vivo.
    CONCLUSIONS: The distinct expression responses amongst strains indicate that bai genes are regulated differently. CA promoted bai operon gene expression and the 7-dehydroxylating activity in C. scindens strains. Conversely, the in vitro activity of E. muris was promoted only after the addition of cecal content and the isolate did not alter bai gene expression in response to CA. The accessory gene baiJ was only upregulated in the C. scindens ATCC 35704 strain, implying mechanistic differences amongst isolates. Interestingly, the human-derived C. scindens strains were also capable of 7-dehydroxylating murine bile acids (muricholic acids) to a limited extent. This study shows novel 7-dehydroxylation activity in vitro resulting from the presence of CA and suggests distinct bai gene expression across bacterial species.
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  • 文章类型: Journal Article
    原发性胆汁性胆管炎(PBC)是一种慢性自身免疫性胆汁淤积性疾病,其特征是肝内小胆管的破坏。会进展为肝硬化.治疗PBC的金标准是熊去氧胆酸(UDCA),这在所有PBC患者中都适用,因为它不仅改善了生化指标,还改善了患者的生存率。鉴定处于危险中的患者的一个重要里程碑是评估对UDCA的生化反应。对治疗有反应的患者比对治疗无反应的患者具有更低的肝事件发生率和更好的预后。可以使用几种评分系统来评估反应并识别将从二线治疗中受益的非反应者。奥贝胆酸(OCA)是目前唯一批准的PBC二线治疗药物,对UDCA治疗无应答者或患者有效,不耐受UDCA治疗的患者。然而,OCA在晚期肝硬化和门脉高压症是禁忌的。此外,瘙痒可能是OCA给药的限制因素。贝特已经显示了有希望的数据,支持它们在对UDCA无反应者中的使用,因为它们改善了生化参数和弹性成像结果,并具有可能的止痒作用。因此,三重治疗的想法似乎很有趣。临床研究集中在其他几组药物:过氧化物酶体增殖物激活受体(PPAR)δ-和α/δ激动剂,非甾体类法尼醇X受体激动剂,成纤维细胞生长因子19调节剂,和烟酰胺腺嘌呤二核苷酸磷酸氧化酶1和4的抑制剂。
    Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease characterized by the destruction of the small intrahepatic bile ducts, which can progress to liver cirrhosis. The gold standard in the treatment of PBC is ursodeoxycholic acid (UDCA), which is indicated in all patients with PBC because it improves not only biochemical parameters but also patients\' survival. An important milestone in the identification of patients at risk is the assessment of biochemical response to UDCA. Patients who respond to treatment have a lower incidence of hepatic events and better prognosis than patients who do not. Several scoring systems can be used to assess the response and identify non-responders who will benefit from second-line treatment. Obeticholic acid (OCA) is currently the only approved second-line treatment for PBC, which is effective for non-responders to UDCA therapy or patients, who have not tolerated UDCA therapy. However, OCA is contraindicated in advanced liver cirrhosis and portal hypertension. Moreover, pruritus may be a limiting factor for the administration of OCA. Fibrates have shown promising data supporting their use in non-responders to UDCA because they improve the biochemical parameters and elastographic findings and have possible antipruritic effects. Therefore, the idea of a triple treatment seems interesting. Clinical research is focusing on several other groups of drugs: peroxisome proliferator-activated receptor (PPAR) δ- and α/δ agonists, non-steroidal farnesoid X receptor agonists, fibroblast growth factor 19 modulators, and inhibitors of nicotinamide adenine dinucleotide phosphate oxidase 1 and 4.
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  • 文章类型: Journal Article
    本荟萃分析的目的是评估熊去氧胆酸(UDCA)在非酒精性脂肪性肝病(NAFLD)治疗中的有效性。
    电子数据库,如PubMed,Embase,Scopus,和CochraneLibrary彻底寻找确定熊去氧胆酸(UDCAs)对NAFLD患者血清肝功能测试有效性的随机对照试验。筛选后,共纳入7项随机对照试验.利用固定效果模型,在R版本4.3.1中进行了定量数据合成.
    荟萃分析显示丙氨酸转氨酶(ALT)显着降低(p≤0.0001),天冬氨酸转氨酶(p=0.0009),UDCA治疗后的γ-谷氨酰转移酶(GGT)(p≤0.0001)。然而,未发现胆红素(p=0.6989)和碱性磷酸酶(ALP)(p=0.1172)水平显著下降.通过消除一些偏倚的研究,敏感性分析成功地证明了天冬氨酸转氨酶和ALP的异质性显着降低。在通过剂量进行亚组分析时也观察到了这一点。
    熊去氧胆酸对诊断为NAFLD的患者有益,因为它显著降低了天冬氨酸转氨酶,ALT和GGT水平。然而,未来需要进行更多的随机对照试验,以提高明显发现的确定性.
    这项荟萃分析加强了关于AST降低的证据,ALT,和GGT水平观察到熊去氧胆酸治疗NAFLD患者通过汇集数据从最新的RCTs,从而证明其肝脏保护作用,可有利于预防相关并发症。
    帕特尔VS,马哈茂德SF,BhattKH,etal.熊去氧胆酸治疗非酒精性脂肪性肝病的有效性:系统评价和Meta分析。欧亚J肝胃肠病2024;14(1):92-98。
    UNASSIGNED: This meta-analysis\'s objective was to assess the effectiveness of ursodeoxycholic acid (UDCA) in the management of nonalcoholic fatty liver disease (NAFLD).
    UNASSIGNED: Electronic databases like PubMed, Embase, Scopus, and Cochrane Library were thoroughly looked for randomized controlled trials determining ursodeoxycholic acid\'s (UDCAs) effectiveness on the serum liver function tests in NAFLD patients. After screening, seven randomized controlled trials were incorporated overall. Utilizing a fixed effects model, quantitative data synthesis was performed in R version 4.3.1.
    UNASSIGNED: The meta-analysis showed significant reductions in alanine transaminase (ALT) (p ≤ 0.0001), aspartate transaminase (p = 0.0009), and gamma-glutamyl transferase (GGT) (p ≤ 0.0001) after UDCA therapy. However, significant reductions in bilirubin (p = 0.6989) and alkaline phosphatase (ALP) (p = 0.1172) levels were not noted. Sensitivity analysis by removing the studies with some concerns of bias was successful in demonstrating a remarkable reduction in heterogeneity for aspartate transaminase and ALP, which was also observed while performing the subgroup analyses via dosage.
    UNASSIGNED: Ursodeoxycholic acid was beneficial in patients diagnosed with NAFLD as it significantly reduced aspartate transaminase, ALT and GGT levels. However, more randomized controlled trials are required to be conducted in the future to increase the certainty of the evident findings.
    UNASSIGNED: This meta-analysis strengthens the evidence about the reductions in AST, ALT, and GGT levels observed with ursodeoxycholic acid therapy in NAFLD patients by pooling the data together from the latest RCTs thus proving its hepatoprotective effects which can be beneficial in preventing the associated complications.
    UNASSIGNED: Patel VS, Mahmood SF, Bhatt KH, et al. Ursodeoxycholic Acid\'s Effectiveness in the Management of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Euroasian J Hepato-Gastroenterol 2024;14(1):92-98.
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  • 文章类型: Journal Article
    柑橘素缺乏症(CD)是一种隐性疾病,由编码线粒体天冬氨酸-谷氨酸转运蛋白的SLC25A13基因中的序列变异引起的肝病。CD表现为不同的年龄依赖性表型,并影响关键的肝脏代谢途径,包括苹果酸-天冬氨酸-穿梭,糖酵解,糖异生,从头脂肪生成和三羧酸和尿素循环。尽管CD的确切病理生理学尚不清楚,由于NADH穿梭缺陷和PPARα下调,葡萄糖和脂肪酸作为能源的使用受损,分别,表明CD肝细胞中明显的能量缺乏。本综述总结了CD的可用和潜在治疗方法的当前趋势。对CD患者的基线建议是饮食管理,通常已经作为一种自我选择的食物偏好存在,包括富含蛋白质和脂肪的食物,避免多余的碳水化合物。目前,肝移植仍然是治疗严重CD病例的唯一选择.我们广泛的文献综述表明,中链甘油三酯(MCT)是所有年龄段中使用最广泛的CD治疗方法。MCT可以通过快速为肝脏提供能量来有效改善疾病表型的症状,恢复氧化还原平衡和诱导脂肪生成。相比之下,丙酮酸钠恢复糖酵解并显示出最初的临床前前景,然而,在成人CD患者中疗效有限。熊去氧胆酸,氮清除剂和L-精氨酸治疗可有效解决特定的病理生理方面,例如胆汁淤积和高氨血症,通常与其他药物联合使用。最后,未来的可能性,包括恢复氧化还原平衡,补充氨基酸,增强生物能学,还讨论了改善尿道发育和基于mRNA/DNA的基因治疗。
    Citrin deficiency (CD) is a recessive, liver disease caused by sequence variants in the SLC25A13 gene encoding a mitochondrial aspartate-glutamate transporter. CD manifests as different age-dependent phenotypes and affects crucial hepatic metabolic pathways including malate-aspartate-shuttle, glycolysis, gluconeogenesis, de novo lipogenesis and the tricarboxylic acid and urea cycles. Although the exact pathophysiology of CD remains unclear, impaired use of glucose and fatty acids as energy sources due to NADH shuttle defects and PPARα downregulation, respectively, indicates evident energy deficit in CD hepatocytes. The present review summarizes current trends on available and potential treatments for CD. Baseline recommendation for CD patients is dietary management, often already present as a self-selected food preference, that includes protein and fat-rich food, and avoidance of excess carbohydrates. At present, liver transplantation remains the sole curative option for severe CD cases. Our extensive literature review indicated medium-chain triglycerides (MCT) as the most widely used CD treatment in all age groups. MCT can effectively improve symptoms across disease phenotypes by rapidly supplying energy to the liver, restoring redox balance and inducing lipogenesis. In contrast, sodium pyruvate restored glycolysis and displayed initial preclinical promise, with however limited efficacy in adult CD patients. Ursodeoxycholic acid, nitrogen scavengers and L-arginine treatments effectively address specific pathophysiological aspects such as cholestasis and hyperammonemia and are commonly administered in combination with other drugs. Finally, future possibilities including restoring redox balance, amino acid supplementation, enhancing bioenergetics, improving ureagenesis and mRNA/DNA-based gene therapy are also discussed.
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  • 文章类型: Journal Article
    背景:这项研究的目的是,首先,通过测量胎儿PR间期,探讨妊娠肝内胆汁淤积症(ICP)患者胎儿房室传导的差异;评价熊去氧胆酸(UDCA)治疗对ICP患者胎儿PR间期的影响。
    方法:该研究包括42名ICP患者和48名健康孕妇。进行胎儿超声心动图以测量机械PR间隔。比较两组胎儿PR间期及临床特点。评估了UDCA治疗对ICP患者胎儿PR间期的影响。
    结果:在ICP患者中,观察到的胎儿PR间隔明显长于对照组(123.21±8.54vs.115.13±5.95ms,p<0.001)。在ICP组中,胎儿PR间期与孕妇空腹总胆汁酸水平(TBA)呈正相关(r=0.514,p=0.001)。ICP患者接受UDCA治疗一周后,PR间隔比以前短,虽然减少没有统计学意义(120.98±6.70vs.123.21±8.54ms,p=0.095)。在重度ICP患者中(TBA&gt;40mmol/L,n=10),在用UDCA治疗后观察到胎儿PR间期显着降低(127,5ms[IQR,118,0-134,75]之前vs.122ms[IQR,109,5-126,5]之后,p=0,037)。
    结论:ICP患者胎儿PR间期增加与母体血清TBA浓度相关。用UDCA治疗可能对胎儿房室传导系统具有有限的积极作用。在胆汁酸水平较高的患者中,UDCA对胎儿PR间期的有益作用可能更为明显。
    BACKGROUND: The aim of this study was, first, to investigate the difference in fetal atrioventricular conduction in patients with and without intrahepatic cholestasis of pregnancy (ICP) by measuring the fetal PR interval; second, to evaluate the altering effect of ursodeoxycholic acid (UDCA) treatment on the fetal PR interval in ICP patients.
    METHODS: The study consisted of 42 ICP patients and 48 healthy pregnant women. Fetal echocardiography was performed to measure the mechanical PR interval. The fetal PR interval and the clinical characteristics were compared between the two groups. The effect of UDCA treatment on the fetal PR interval in ICP patients was evaluated.
    RESULTS: In ICP patients, significantly longer fetal PR intervals were observed than in the control group (123.21 ± 8.54 vs. 115.13 ± 5.95 ms, p < 0.001). In the ICP group, there was a positive correlation between the fetal PR interval and maternal fasting total bile acid (TBA) levels (r = 0.514, p = 0.001). After 1 week of treatment with UDCA in patients with ICP, the PR interval was shorter than before, although the reduction was not statistically significant (120.98 ± 6.70 vs. 123.21 ± 8.54 ms, p = 0.095). In patients with severe ICP (TBA >40 mmol/L, n = 10), a significant reduction in the fetal PR interval was observed after treatment with UDCA (127.5 ms [IQR, 118.0-134.75] before vs. 122 ms [IQR, 109.5-126.5] after, p = 0.037).
    CONCLUSIONS: Fetal PR interval increased in ICP patients in correlation with maternal serum TBA concentration. Treatment with UDCA may have limited positive effects on the fetal AV conduction system. The beneficial effects of UDCA on the fetal PR interval may be more pronounced in patients with higher bile acid levels.
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