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Emerging role of immunotherapy for cancer as a major cause of drug-induced liver injury 癌症免疫疗法正在成为药物性肝损伤的主要原因。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-06-08 DOI: 10.1016/j.aohep.2024.101520
Nelia Hernandez, Fernando Bessone, Raul Andrade
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引用次数: 0
Hepatitis C virus NS5A and core protein induce fibrosis-related genes regulation on Huh7 cells through activation of LX2 cells 丙型肝炎病毒 NS5A 和核心蛋白通过激活 LX2 细胞诱导 Huh7 细胞纤维化相关基因的调控。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-06-07 DOI: 10.1016/j.aohep.2024.101517

Introduction and Objectives

Liver fibrosis remains a complication derived from a chronic Hepatitis C Virus (HCV) infection even when it is resolved, and no liver antifibrotic drug has been approved. Molecular mechanisms on hepatocytes and activation of hepatic stellate cells (HSCs) play a central role in liver fibrogenesis. To elucidate molecular mechanisms, it is important to analyze pathway regulation during HSC activation and HCV infection.

Materials and Methods

We evaluate the fibrosis-associated molecular mechanisms during a co-culture of human HSCs (LX2), with human hepatocytes (Huh7) that express HCV NS5A or Core protein. We evaluated LX2 activation induced by HCV NS5A or Core expression in Huh7 cells during co-culture. We determined a fibrosis-associated gene expression profile in Huh7 that expresses NS5A or Core proteins during the co-culture with LX2.

Results

We observed that NS5A induced 8.3-, 6.7- and 4-fold changes and that Core induced 6.5-, 1.8-, and 6.2-fold changes in the collagen1, TGFβ1, and timp1 gene expression, respectively, in LX2 co-cultured with transfected Huh7. In addition, NS5A induced the expression of 30 genes while Core induced 41 genes and reduced the expression of 30 genes related to fibrosis in Huh7 cells during the co-culture with LX2, compared to control. The molecular pathways enriched from the gene expression profile were involved in TGFB signaling and the organization of extracellular matrix.

Conclusions

We demonstrated that HCV NS5A and Core protein expression regulate LX2 activation. NS5A and Core-induced LX2 activation, in turn, regulates diverse fibrosis-related gene expression at different levels in Huh7, which can be further analyzed as potential antifibrotic targets during HCV infection.

引言和目的:肝纤维化仍然是慢性丙型肝炎病毒(HCV)感染的一种并发症,即使在病情得到缓解的情况下也是如此,目前还没有抗肝纤维化的药物获得批准。肝细胞的分子机制和肝星状细胞(HSCs)的活化在肝纤维化中起着核心作用。要阐明分子机制,就必须分析造血干细胞活化和HCV感染过程中的通路调控:我们评估了人造血干细胞(LX2)与表达 HCV NS5A 或核心蛋白的人肝细胞(Huh7)共培养过程中纤维化相关的分子机制。我们评估了Huh7细胞在共培养过程中因表达HCV NS5A或Core而诱导的LX2活化。我们确定了与 LX2 共培养过程中表达 NS5A 或 Core 蛋白的 Huh7 细胞中纤维化相关基因的表达谱:结果:我们观察到,在 LX2 与转染的 Huh7 共培养过程中,NS5A 可诱导胶原 1、TGFβ1 和 timp1 基因表达分别发生 8.3 倍、6.7 倍和 4 倍的变化,Core 可诱导胶原 1、TGFβ1 和 timp1 基因表达分别发生 6.5 倍、1.8 倍和 6.2 倍的变化。此外,与对照组相比,NS5A诱导了30个基因的表达,而Core诱导了41个基因的表达,同时降低了30个与Huh7细胞纤维化相关的基因的表达。从基因表达谱中富集的分子通路参与了TGFB信号转导和细胞外基质的组织:我们证明了HCV NS5A和核心蛋白的表达调控LX2的活化。NS5A诱导的LX2活化反过来又在不同水平上调控Huh7中多种纤维化相关基因的表达,这些基因可被进一步分析为HCV感染期间潜在的抗纤维化靶点。
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引用次数: 0
Frailty and sarcopenia in patients with acute-on-chronic liver failure: Assessment and risk in the liver transplant setting 急性-慢性肝衰竭患者的虚弱和肌肉疏松症:肝移植环境中的评估和风险。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-06-07 DOI: 10.1016/j.aohep.2024.101515
Isabel Campos-Varela , Lluis Castells , Sergi Quiroga , Victor Vargas , Macarena Simon-Talero

Frailty and sarcopenia are well-recognized factors related to worse outcomes in patients with cirrhosis, including liver transplant (LT) candidates. Implications of pre-LT functional and muscle deterioration also affect post-LT outcomes. Patients with cirrhosis and acute-on-chronic liver failure (ACLF) have a lower survival rate, both before and after LT. There is a need to better identify those patients with ACLF who would benefit from LT. This review aims to present the available data about frailty and sarcopenia in patients with ACLF in the LT setting. An exhaustive review of the published literature was conducted. Data regarding frailty and sarcopenia in LT candidates with ACLF are scarce and heterogeneous. Studies evaluating frailty and sarcopenia in critically ill patients outside the liver literature are also presented in this review to enrich the knowledge of this field in expansion. Frailty and sarcopenia seem to contribute to worse outcomes in LT candidates with ACLF, both before and after LT. Sarcopenia evaluation may be the most prudent approach for those very sick patients. Skeletal muscle index assessed by computed tomography is recommended to evaluate sarcopenia. The role of muscle ultrasound and bioelectrical impedance analysis is to be determined. Frailty and sarcopenia are crucial factors to consider on a case-by-case basis in LT candidates with ACLF to improve patient outcomes.

衰弱和肌肉疏松症是肝硬化患者(包括肝移植候选者)预后较差的公认因素。肝移植前的功能和肌肉衰退也会影响肝移植后的预后。肝硬化和急性慢性肝衰竭(ACLF)患者在肝移植前后的存活率都较低。有必要更好地确定哪些 ACLF 患者可从 LT 中获益。本综述旨在介绍在LT情况下ACLF患者的虚弱和肌肉疏松症的现有数据。我们对已发表的文献进行了详尽的回顾。有关前交叉韧带纤维化 LT 候选者的虚弱和肌肉疏松症的数据非常稀少,而且各不相同。本综述还介绍了肝脏文献以外的评估重症患者虚弱和肌肉疏松症的研究,以丰富这一领域的知识。虚弱和肌肉疏松症似乎会导致患有 ACLF 的 LT 候选者在 LT 前后的预后更差。对于重症患者来说,评估肌肉疏松症可能是最稳妥的方法。建议使用计算机断层扫描评估骨骼肌指数来评估肌肉疏松症。肌肉超声波和生物电阻抗分析的作用尚待确定。对于患有前列腺增生症的腰椎间盘突出症患者来说,虚弱和肌肉疏松症是需要逐一考虑的关键因素,这样才能更好地改善患者的预后。
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引用次数: 0
Palliative care and end stage liver disease: A cohort analysis of palliative care use and factors associated with referral 姑息关怀与终末期肝病:对姑息关怀使用情况及转诊相关因素的队列分析。
IF 3.7 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-06-06 DOI: 10.1016/j.aohep.2024.101518
Hugo M Oliveira , Helena Pessegueiro Miranda , Francisca Rego , Rui Nunes

Introduction and Objectives

Prevalence and mortality of chronic liver disease have risen significantly. In end stage liver disease, the survival of patients is approximately two years. Despite the poor prognosis and high symptom burden of these patients, integration of palliative care is limited. We aim to assess associated factors and trends in palliative care use in recent years.

Materials and Methods

A Multicenter retrospective cohort of patients with end stage liver disease who suffered in-hospital mortality between 2017 and 2019. Information regarding patient demographics, hospital characteristics, comorbidities, etiology, decompensations, and interventions was collected. Two-sided tests and logistic regression analysis were used to identify factors associated with palliative care use.

Results

A total of 201 patients were analyzed, with a yearly increase in palliative care consultation: 26.7 % in 2017 to 38.3 % in 2019. Patients in palliative care were older (65.72 ± 11.70 vs. 62.10 ± 11.44; p = 0.003), had a lower Karnofsky functionality scale (χ=18.104; p = 0.000) and had higher rates of hepatic encephalopathy (32.1 % vs. 17.4 %, p = 0.007) and hepatocarcinoma (61.7 % vs. 26.2 %; p = 0.000). No differences were found for Model for End-stage Liver Disease (19.28 ± 6.60 vs. 19,90 ± 5.78; p = 0.507) or Child-Pugh scores (p = 0.739). None of the patients who die in the intensive care unit receive palliative care (0 % vs 31.6 %; p = 0.000). Half of the palliative care consultations occurred 6,5 days before death.

Conclusions

Palliative care use differs based on demographics, disease complications, and severity. Despite its increasing implementation, palliative care intervention occurs late. Future investigations should identify approaches to achieve an earlier and concurrent care model.

导言和目标:慢性肝病的发病率和死亡率显著上升。晚期肝病患者的生存期约为两年。尽管这些患者的预后较差,症状负担较重,但姑息治疗的整合却很有限。我们旨在评估近年来使用姑息治疗的相关因素和趋势:多中心回顾性队列,对象为2017-2019年间院内死亡的终末期肝病患者。收集了有关患者人口统计学、医院特征、合并症、病因、失代偿和干预措施的信息。采用双侧检验和逻辑回归分析来确定与姑息治疗使用相关的因素:共分析了201名患者,姑息治疗就诊率逐年上升:2017年为26.7%,2019年为38.3%。接受姑息治疗的患者年龄较大(65,72±11,70 vs. 62,10±11,44;p=0,003),卡诺夫斯基功能评分较低(χ=18.104;p=0.000),肝性脑病(32.1% vs. 17.4%,p=0.007)和肝癌(61.7% vs. 26.2%;p=0.000)发生率较高。终末期肝病模型(19,28±6,60 vs. 19,90±5,78;p=0,507)或 Child-Pugh 评分(p=0,739)没有发现差异。在重症监护室死亡的患者中,没有一人接受姑息治疗(0% vs 31.6%;P=0.000)。半数姑息治疗咨询发生在死亡前6.5天:姑息治疗的使用因人口统计学、疾病并发症和严重程度而异。尽管姑息关怀的实施越来越多,但其干预却很晚。未来的调查应确定如何实现更早和同步的姑息关怀模式。
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引用次数: 0
The steatosis-associated fibrosis estimator (SAFE) outperformed the FIB-4 score in screening the population for liver disease 在筛查人群肝病方面,脂肪变性相关纤维化估算器(SAFE)优于 FIB-4 评分。
IF 3.8 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-06-06 DOI: 10.1016/j.aohep.2024.101516
Mingkai Li , Ying Lin , Hongsheng Yu , Weichun Lin , Jianning Chen , Yidong Yang , Bin Wu

Introduction and Objectives

Assessing fibrosis risk noninvasively is essential. The steatosis-associated fibrosis estimator (SAFE) score shows promise but needs validation.

Patients and Methods

This was a three-part study. In part 1, we compared the SAFE score with the Fibrosis-4 (FIB-4) and NAFLD fibrosis score (NFS) in the National Health and Nutrition Examination Survey (NHANES) cohort (2017–2020), using transient elastography (TE) as screening reference. In part 2, we examined patients who underwent liver biopsies at an Asian center between 2018 and 2020 to assess these models in various liver diseases. In part 3, the SAFE score was applied to adults in the NHANES cohort (1999–2016) to assess the correlation with mortality.

Results

In part 1, we studied 6,677 patients, comprising 595 screening positive (TE ≥8 kPa). SAFE (cutoff 100) displayed a lower proportion of false positives (10.4 %) than FIB-4 (cutoff 1.3) and NFS (cutoff -1.455) (22.1 % and 43.6 %) while retaining a low proportion of false negatives (5.5 %). In part 2, SAFE outperformed FIB-4 (P = 0.04) and NFS (P = 0.04) in staging significant fibrosis (≥S2) in NAFLD and had similar accuracies in other etiologies. In part 3, the FIB-4, NFS, and SAFE score were associated with all-cause mortality in the general population, with c-statistics of 0.738, 0.736, and 0.759, respectively.

Conclusions

The SAFE score reduced futile referrals more effectively than FIB-4 without raising the missed TE ≥ 8 kPa rate. It correlated with all-cause mortality in the general population and excelled in staging significant fibrosis in NAFLD.

导言和目标:无创评估纤维化风险至关重要。脂肪变性相关纤维化估计器(SAFE)评分显示了前景,但需要验证:这是一项由三部分组成的研究。在第一部分中,我们将 SAFE 评分与美国国家健康与营养调查(NHANES)队列(2017-2020 年)中的纤维化-4(FIB-4)和非酒精性脂肪肝纤维化评分(NFS)进行了比较,并使用瞬态弹性成像(TE)作为筛查参考。在第 2 部分中,我们研究了 2018 年至 2020 年期间在一家亚洲中心接受肝活检的患者,以评估这些模型在各种肝病中的应用情况。在第3部分中,我们将SAFE评分应用于NHANES队列(1999-2016年)中的成年人,以评估其与死亡率的相关性:在第 1 部分中,我们研究了 6,677 名患者,其中包括 595 名筛查阳性(TE ≥8 kPa)患者。SAFE(截断值 100)的假阳性比例(10.4%)低于 FIB-4(截断值 1.3)和 NFS(截断值-1.455)(22.1% 和 43.6%),而假阴性比例较低(5.5%)。在第 2 部分中,SAFE 在对非酒精性脂肪肝的显著纤维化(≥S2)进行分期方面优于 FIB-4(P = 0.04)和 NFS(P = 0.04),而在其他病因方面的准确性相似。在第3部分中,FIB-4、NFS和SAFE评分与普通人群的全因死亡率相关,c统计量分别为0.738、0.736和0.759:结论:与 FIB-4 相比,SAFE 评分能更有效地减少无用转诊,同时不会提高 TE ≥ 8 kPa 的漏诊率。结论:SAFE评分比FIB-4能更有效地减少无用转诊,同时不会提高TE≥8 kPa的漏诊率。
{"title":"The steatosis-associated fibrosis estimator (SAFE) outperformed the FIB-4 score in screening the population for liver disease","authors":"Mingkai Li ,&nbsp;Ying Lin ,&nbsp;Hongsheng Yu ,&nbsp;Weichun Lin ,&nbsp;Jianning Chen ,&nbsp;Yidong Yang ,&nbsp;Bin Wu","doi":"10.1016/j.aohep.2024.101516","DOIUrl":"10.1016/j.aohep.2024.101516","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><p>Assessing fibrosis risk noninvasively is essential. The steatosis-associated fibrosis estimator (SAFE) score shows promise but needs validation.</p></div><div><h3>Patients and Methods</h3><p>This was a three-part study. In part 1, we compared the SAFE score with the Fibrosis-4 (FIB-4) and NAFLD fibrosis score (NFS) in the National Health and Nutrition Examination Survey (NHANES) cohort (2017–2020), using transient elastography (TE) as screening reference. In part 2, we examined patients who underwent liver biopsies at an Asian center between 2018 and 2020 to assess these models in various liver diseases. In part 3, the SAFE score was applied to adults in the NHANES cohort (1999–2016) to assess the correlation with mortality.</p></div><div><h3>Results</h3><p>In part 1, we studied 6,677 patients, comprising 595 screening positive (TE ≥8 kPa). SAFE (cutoff 100) displayed a lower proportion of false positives (10.4 %) than FIB-4 (cutoff 1.3) and NFS (cutoff -1.455) (22.1 % and 43.6 %) while retaining a low proportion of false negatives (5.5 %). In part 2, SAFE outperformed FIB-4 (<em>P</em> = 0.04) and NFS (<em>P</em> = 0.04) in staging significant fibrosis (≥S2) in NAFLD and had similar accuracies in other etiologies. In part 3, the FIB-4, NFS, and SAFE score were associated with all-cause mortality in the general population, with c-statistics of 0.738, 0.736, and 0.759, respectively.</p></div><div><h3>Conclusions</h3><p>The SAFE score reduced futile referrals more effectively than FIB-4 without raising the missed TE ≥ 8 kPa rate. It correlated with all-cause mortality in the general population and excelled in staging significant fibrosis in NAFLD.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 5","pages":"Article 101516"},"PeriodicalIF":3.8,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003107/pdfft?md5=173d10da0767e549ff95b95d6ca9e7dc&pid=1-s2.0-S1665268124003107-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prognostic significance of low hepatic fat content in advanced chronic liver disease: MRI-PDFF insights 晚期慢性肝病肝脏脂肪含量低的预后意义:磁共振成像-PDFF的启示
IF 3.8 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-05-08 DOI: 10.1016/j.aohep.2024.101507
Atsushi Nakamura, Tsubasa Yoshimura, Takeshi Ichikawa, Keiji Okuyama

Introduction and Objectives

The mechanisms of hepatic fat loss in late-stage metabolic dysfunction-associated fatty liver disease (MASLD) are enigmatic and the prognostic significance of low hepatic fat content (LHF) in chronic liver disease (CLD) is unknown. Proton density fat fraction (PDFF), measured by magnetic resonance imaging (MRI), is considered the most accurate noninvasive method for quantifying hepatic fat content. This study aimed to address these issues by evaluating PDFF.

Patients and Methods

This is a single-center, retrospective study involving 762 patients with CLD, measuring liver stiffness (LS) using MR elastography and PDFF using MRI. LHF was defined as a PDFF ≤ 2.7 % and hepatic reserve function was assessed using the albumin-bilirubin (ALBI) score. Multivariate analysis explored associations between variables.

Results

LHF was 27 % in the entire cohort, and PDFF was significantly decreased with LS ≥ 5.5 kPa (p < 0.05). On the multivariate analysis, low body mass index and ALBI score were independently associated with LHF (p < 0.05). In advanced CLD (n = 288), ALBI score and PDFF showed a significant negative correlation regardless of etiology (MASLD/non-MASLD: r= -0.613/-0.233), and the prevalence of LHF increased with progression of ALBI grade (p < 0.01 each). In addition, lower PDFF was associated with increased liver-related and all-cause mortality (p < 0.01), and Cox proportional hazards models extracted LHF as an independent prognostic factor, along with ALBI score and hepatocellular carcinoma (p < 0.05 each).

Conclusions

In ACLD, hepatic reserve dysfunction contributed to hepatic fat loss independent of nutritional status, suggesting that LHF may be a poor prognostic factor in all etiologies.

导言和目标:代谢功能障碍相关性脂肪肝(MASLD)晚期肝脏脂肪减少的机制尚不清楚,慢性肝病(CLD)肝脏脂肪含量低(LHF)的预后意义也不明确。通过磁共振成像(MRI)测量的质子密度脂肪分数(PDFF)被认为是量化肝脏脂肪含量最准确的无创方法。本研究旨在通过评估质子密度脂肪分数来解决这些问题:这是一项涉及 762 名慢性肝病患者的单中心回顾性研究,使用磁共振弹性成像技术测量肝脏硬度(LS),并使用磁共振成像技术测量 PDFF。LHF定义为PDFF≤2.7%,肝储备功能使用白蛋白-胆红素(ALBI)评分进行评估。多变量分析探讨了变量之间的关联:整个队列中,LHF 为 27%,LS ≥ 5.5 kPa 会显著降低 PDFF(p< 0.05)。在多变量分析中,低体重指数和 ALBI 评分与 LHF 独立相关(P< 0.05)。在晚期 CLD(288 人)中,无论病因如何(MASLD/非 MASLD:r= -0.613/-0.233),ALBI 评分和 PDFF 均呈显著负相关,LHF 的发生率随 ALBI 分级的增加而增加(p< 0.01)。此外,较低的PDFF与肝脏相关死亡率和全因死亡率增加有关(P< 0.01),Cox比例危险模型将LHF与ALBI评分和肝细胞癌(P< 0.05)一起提取为独立的预后因素:结论:在 ACLD 中,肝储备功能障碍导致肝脏脂肪流失,而与营养状况无关,这表明 LHF 可能是所有病因的不良预后因素。
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引用次数: 0
Coronary artery disease as a risk factor for metabolic dysfunction-associated steatotic liver disease and liver fibrosis 冠状动脉疾病是代谢功能障碍相关性脂肪性肝病和肝纤维化的危险因素。
IF 3.8 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-05-06 DOI: 10.1016/j.aohep.2024.101511
Luis Vega , Daniela Simian , Abraham I. Gajardo , Marcelo Salinas , Andrea Urra , Máximo Cattaneo , Rosario Pino , Juan P. Roblero , Álvaro Urzúa , Katherine Rojas , Jaime Poniachik

Introduction and Objectives

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are at an increased cardiovascular risk. On the contrary, non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with coronary heart disease (CHD). However, it is not known whether patients with significant CHD show a higher frequency of liver fibrosis. This study aimed to determine the frequency of MASLD and liver fibrosis in patients with CHD and to assess whether coronary stenosis is significantly associated with MASLD and fibrosis.

Patients and Methods

This observational and analytical study included adult patients without any known liver disease who underwent coronary angiography for suspected coronary artery disease (Jul 2021–Jul 2022). The presence of significant CHD (> 50% stenosis of at least one coronary artery) was determined. Liver elastography (FibroScan®) was performed up to 6 months after the coronary angiographic study to determine liver fibrosis, a measurement of liver stiffness (> 6.5 Kpa). Fisher's test, Mann–Whitney U test, and logistic regression models were used (p < 0.05).

Results

The study included 113 patients (76% men, average age: 63 years [standard deviation: 9.9]), of which 72% presented with significant CHD. The prevalence rate of MASLD was 52%. Liver fibrosis was present in 12% of the patients and all patients in the significant CHD group (p = 0.007). An increase in the number of vessels with significant CHD increased the probability of liver fibrosis (odds ratio, 1.79; 95% confidence interval, 1.06–3.04; p = 0.029).

Conclusions

MASLD is highly prevalent in patients with significant CHD but without known liver damage. These data suggest that MASLD and liver fibrosis should be investigated in patients with CHD. The presence of confounding variables, especially the presence of type 2 diabetes mellitus, should be evaluated in further studies.

导言和目标:代谢功能障碍相关性脂肪性肝病(MASLD)患者的心血管风险增加。相反,非酒精性脂肪肝(NAFLD)在冠心病(CHD)患者中发病率很高。然而,尚不清楚患有严重冠心病的患者是否会出现更高频率的肝纤维化。本研究旨在确定冠心病患者中MASLD和肝纤维化的发生频率,并评估冠状动脉狭窄是否与MASLD和肝纤维化显著相关:这项观察和分析研究纳入了无任何已知肝病的成年患者,这些患者因怀疑患有冠状动脉疾病而接受了冠状动脉造影术(2021年7月至2022年7月)。确定是否存在明显的冠心病(至少一条冠状动脉狭窄>50%)。在冠状动脉造影检查后 6 个月内进行肝脏弹性成像(FibroScan®),以确定肝脏纤维化程度,这是肝脏硬度(> 6.5 Kpa)的测量值。采用了费雪检验、曼-惠特尼 U 检验和逻辑回归模型(pResults:研究共纳入 113 名患者(76% 为男性,平均年龄:63 岁[标准差:9.9]),其中 72% 的患者伴有明显的心脏病。MASLD的发病率为52%。12%的患者存在肝纤维化,而在严重心脏病组中,所有患者都存在肝纤维化(P=0.007)。伴有明显冠状动脉缺血的血管数量的增加会增加肝纤维化的几率(几率比,1.79;95% 置信区间,1.06-3.04;P=0.029):MASLD在有明显心脏病但未发现肝损伤的患者中发病率很高。这些数据表明,MASLD 和肝纤维化应在冠心病患者中进行调查。在进一步的研究中,应评估是否存在混杂变量,尤其是是否存在2型糖尿病。
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引用次数: 0
Genome-wide DNA methylation and transcriptomic analysis of liver tissues subjected to early ischemia/reperfusion injury upon human liver transplantation 对人体肝移植后早期缺血再灌注损伤的肝组织进行全基因组DNA甲基化和转录组分析。
IF 3.8 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-05-06 DOI: 10.1016/j.aohep.2024.101506
Pablo J. Giraudi , Allen A. Laraño , Simeone Dal Monego , Riccardo Pravisani , Deborah Bonazza , Gabriel Gondolesi , Claudio Tiribelli , Francisco Baralle , Umberto Baccarani , Danilo Licastro

Introduction and Objectives

Epigenetic changes represent a mechanism connecting external stresses with long-term modifications of gene expression programs. In solid organ transplantation, ischemia-reperfusion injury (IRI) appears to induce epigenomic changes in the graft, although the currently available data are extremely limited. The present study aimed to characterize variations in DNA methylation and their effects on the transcriptome in liver transplantation from brain-dead donors.

Patients and Methods

12 liver grafts were evaluated through serial biopsies at different timings in the procurement-transplantation process: T0 (warm procurement, in donor), T1 (bench surgery), and T2 (after reperfusion, in recipient). DNA methylation (DNAm) and transcriptome profiles of biopsies were analyzed using microarrays and RNAseq.

Results

Significant variations in DNAm were identified, particularly between T2 and T0. Functional enrichment of the best 1000 ranked differentially methylated promoters demonstrated that 387 hypermethylated and 613 hypomethylated promoters were involved in spliceosomal assembly and response to biotic stimuli, and inflammatory immune responses, respectively. At the transcriptome level, T2 vs. T0 showed an upregulation of 337 and downregulation of 61 genes, collectively involved in TNF-α, NFKB, and interleukin signaling. Cell enrichment analysis individuates macrophages, monocytes, and neutrophils as the most significant tissue-cell type in the response.

Conclusions

In the process of liver graft procurement-transplantation, IRI induces significant epigenetic changes that primarily act on the signaling pathways of inflammatory responses dependent on TNF-α, NFKB, and interleukins. Our DNAm datasets are the early IRI methylome literature and will serve as a launch point for studying the impact of epigenetic modification in IRI.

引言和目的:表观遗传变化是连接外部压力与基因表达程序长期改变的一种机制。在实体器官移植中,缺血再灌注损伤(IRI)似乎会诱导移植物发生表观基因组变化,但目前可用的数据极为有限。本研究旨在描述脑死亡供体肝移植中DNA甲基化的变化及其对转录组的影响。患者和方法:在采购-移植过程的不同时间段,通过连续活检对12例肝移植进行了评估:T0(热采购,供体)、T1(台式手术)和T2(再灌注后,受体)。使用芯片和 RNAseq 对活检组织的 DNA 甲基化(DNAm)和转录组图谱进行了分析:结果:DNAm发生了显著变化,尤其是在T2和T0之间。对排名前1000位的差异甲基化启动子进行功能富集后发现,387个高甲基化启动子和613个低甲基化启动子分别参与剪接体组装、对生物刺激的反应和炎症免疫反应。在转录组水平上,T2 与 T0 相比,上调了 337 个基因,下调了 61 个基因,这些基因共同参与 TNF-α、NFKB 和白细胞介素信号转导。细胞富集分析显示,巨噬细胞、单核细胞和中性粒细胞是反应中最重要的组织细胞类型:结论:在肝脏移植过程中,IRI诱导了显著的表观遗传变化,这些变化主要作用于依赖于TNF-α、NFKB和白细胞介素的炎症反应信号通路。我们的 DNAm 数据集是早期的 IRI 甲基组文献,将成为研究 IRI 中表观遗传修饰影响的起点。
{"title":"Genome-wide DNA methylation and transcriptomic analysis of liver tissues subjected to early ischemia/reperfusion injury upon human liver transplantation","authors":"Pablo J. Giraudi ,&nbsp;Allen A. Laraño ,&nbsp;Simeone Dal Monego ,&nbsp;Riccardo Pravisani ,&nbsp;Deborah Bonazza ,&nbsp;Gabriel Gondolesi ,&nbsp;Claudio Tiribelli ,&nbsp;Francisco Baralle ,&nbsp;Umberto Baccarani ,&nbsp;Danilo Licastro","doi":"10.1016/j.aohep.2024.101506","DOIUrl":"10.1016/j.aohep.2024.101506","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><p>Epigenetic changes represent a mechanism connecting external stresses with long-term modifications of gene expression programs. In solid organ transplantation, ischemia-reperfusion injury (IRI) appears to induce epigenomic changes in the graft, although the currently available data are extremely limited. The present study aimed to characterize variations in DNA methylation and their effects on the transcriptome in liver transplantation from brain-dead donors.</p></div><div><h3>Patients and Methods</h3><p>12 liver grafts were evaluated through serial biopsies at different timings in the procurement-transplantation process: T0 (warm procurement, in donor), T1 (bench surgery), and T2 (after reperfusion, in recipient). DNA methylation (DNAm) and transcriptome profiles of biopsies were analyzed using microarrays and RNAseq.</p></div><div><h3>Results</h3><p>Significant variations in DNAm were identified, particularly between T2 and T0. Functional enrichment of the best 1000 ranked differentially methylated promoters demonstrated that 387 hypermethylated and 613 hypomethylated promoters were involved in spliceosomal assembly and response to biotic stimuli, and inflammatory immune responses, respectively. At the transcriptome level, T2 vs. T0 showed an upregulation of 337 and downregulation of 61 genes, collectively involved in TNF-α, NFKB, and interleukin signaling. Cell enrichment analysis individuates macrophages, monocytes, and neutrophils as the most significant tissue-cell type in the response.</p></div><div><h3>Conclusions</h3><p>In the process of liver graft procurement-transplantation, IRI induces significant epigenetic changes that primarily act on the signaling pathways of inflammatory responses dependent on TNF-α, NFKB, and interleukins. Our DNAm datasets are the early IRI methylome literature and will serve as a launch point for studying the impact of epigenetic modification in IRI.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 4","pages":"Article 101506"},"PeriodicalIF":3.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003004/pdfft?md5=06f4462790d874b8def1ec8c6ecc14ac&pid=1-s2.0-S1665268124003004-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Utilizing a novel MRI technique to identify adverse muscle composition in end-stage liver disease: A pilot study 利用新型磁共振成像技术识别终末期肝病患者的不良肌肉成分:试点研究
IF 3.8 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-05-06 DOI: 10.1016/j.aohep.2024.101508
Avesh J. Thuluvath , Mikael F. Forsgren , Daniela P. Ladner , Amit D. Tevar , Andres Duarte-Rojo

Introduction and Objectives

Sarcopenia is a common complication of end-stage liver disease (ESLD), but its exact relationship to myosteatosis and frailty remains unclear. In this pilot study, we tested the feasibility of a specialized MRI protocol and automated image analysis in patients with ESLD.

Materials and Methods

In a single-center prospective study, adult liver transplant candidates with ESLD underwent assessment of muscle composition between 3/2022 and 6/2022 using the AMRA® MAsS Scan. The primary outcome of interest was feasibility of the novel MRI technique in patients with ESLD. We also tested if thigh muscle composition correlated with validated measures of frailty and sarcopenia.

Results

Eighteen subjects (71 % male, mean age 59 years) were enrolled. The most common etiologies of cirrhosis were alcohol-related liver disease (44 %) and non-alcohol-associated fatty liver disease (33 %), with a mean MELD-Na of 13 (± 4). The mean time needed to complete the MRI protocol was 14.9 min and only one patient could not complete it due to metal hardware in both knees. Forty-one percent of patients had adverse muscle composition (high thigh fat infiltration and low-fat free muscle volume) and these patients were more likely to have undergone a recent large volume paracentesis (43 % vs. 0 %, p < 0.02). The adverse muscle composition group performed significantly worse on the 6-minute walk test compared to the remainder of the cohort (379 vs 470 m, p < 0.01).

Conclusions

The AMRA® MAsS Scan is feasible to perform in patients with ESLD and can be used to quantify myosteatosis, a marker of muscle quality and potentially muscle functionality in ESLD.

导言与目的:肌肉疏松症是终末期肝病(ESLD)的常见并发症,但其与肌骨软化症和虚弱的确切关系仍不清楚。在这项试验性研究中,我们测试了针对 ESLD 患者的专门磁共振成像方案和自动图像分析的可行性:在一项单中心前瞻性研究中,患有 ESLD 的成人肝移植候选者在 2022 年 3 月 3 日至 2022 年 6 月 6 日期间使用 AMRA® MAsS 扫描仪接受了肌肉成分评估。主要研究结果是新型磁共振成像技术在 ESLD 患者中的可行性。我们还测试了大腿肌肉成分是否与虚弱和肌肉疏松症的有效测量指标相关:共招募了 18 名受试者(71% 为男性,平均年龄 59 岁)。最常见的肝硬化病因是酒精相关性肝病(44%)和非酒精相关性脂肪肝(33%),平均 MELD-Na 为 13(± 4)。完成核磁共振成像方案所需的平均时间为14.9分钟,只有一名患者因双膝部有金属硬件而无法完成。41%的患者肌肉成分不良(大腿脂肪浸润高,游离脂肪肌肉体积低),这些患者更有可能在近期接受过大容量旁路穿刺术(43% 对 0%,P 结论:对 ESLD 患者进行 AMRA® MAsS 扫描是可行的,可用于量化肌骨质疏松症,这是 ESLD 患者肌肉质量和潜在肌肉功能的标志。
{"title":"Utilizing a novel MRI technique to identify adverse muscle composition in end-stage liver disease: A pilot study","authors":"Avesh J. Thuluvath ,&nbsp;Mikael F. Forsgren ,&nbsp;Daniela P. Ladner ,&nbsp;Amit D. Tevar ,&nbsp;Andres Duarte-Rojo","doi":"10.1016/j.aohep.2024.101508","DOIUrl":"10.1016/j.aohep.2024.101508","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><p>Sarcopenia is a common complication of end-stage liver disease (ESLD), but its exact relationship to myosteatosis and frailty remains unclear. In this pilot study, we tested the feasibility of a specialized MRI protocol and automated image analysis in patients with ESLD.</p></div><div><h3>Materials and Methods</h3><p>In a single-center prospective study, adult liver transplant candidates with ESLD underwent assessment of muscle composition between 3/2022 and 6/2022 using the AMRA® MAsS Scan. The primary outcome of interest was feasibility of the novel MRI technique in patients with ESLD. We also tested if thigh muscle composition correlated with validated measures of frailty and sarcopenia.</p></div><div><h3>Results</h3><p>Eighteen subjects (71 % male, mean age 59 years) were enrolled. The most common etiologies of cirrhosis were alcohol-related liver disease (44 %) and non-alcohol-associated fatty liver disease (33 %), with a mean MELD-Na of 13 (± 4). The mean time needed to complete the MRI protocol was 14.9 min and only one patient could not complete it due to metal hardware in both knees. Forty-one percent of patients had adverse muscle composition (high thigh fat infiltration and low-fat free muscle volume) and these patients were more likely to have undergone a recent large volume paracentesis (43 % vs<em>.</em> 0 %, <em>p</em> &lt; 0.02). The adverse muscle composition group performed significantly worse on the 6-minute walk test compared to the remainder of the cohort (379 vs 470 m, <em>p</em> &lt; 0.01).</p></div><div><h3>Conclusions</h3><p>The AMRA® MAsS Scan is feasible to perform in patients with ESLD and can be used to quantify myosteatosis, a marker of muscle quality and potentially muscle functionality in ESLD.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 4","pages":"Article 101508"},"PeriodicalIF":3.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1665268124003028/pdfft?md5=0da0cf02e200d9117535a41f0303322b&pid=1-s2.0-S1665268124003028-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140890869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Spending on nucleos(t)ide analogues for hepatitis B in medicaid beneficiaries: 2012-2021 医疗补助受益人用于治疗乙型肝炎的核苷(t)ide 类似物支出:2012-2021 年。
IF 3.8 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-05-06 DOI: 10.1016/j.aohep.2024.101509
Stephen E. Congly , Mayur Brahmania , Carla S. Coffin

Introduction and Objectives

Treatment of chronic hepatitis B (CHB) with nucelos(t)ide analogues (NA) can improve outcomes, but NA treatment is expensive for insurance plans.

Materials and Methods

The Centers for Medicare & Medicaid Services database was assessed from 2012 to 2021 to assess the use of NA for CHB in patients on Medicaid. Data extracted included the number of claims, units, and costs of each agent stratified by originator and generic.

Results

Over the study period, 1.9 billion USD was spent on NA, with spending peaking in 2016 at $289 million US, which has subsequently decreased. Lower expenditures since 2016 have been associated with increased use of generics. The use of generic tenofovir or entecavir led to savings of $669 million US over the study period.

Conclusions

Increased generic use has significantly reduced expenditures for NA drugs; policy shifts towards generic drug use may help with sustainability.

简介和目标:使用核苷类似物(NA)治疗慢性乙型肝炎(CHB)可改善疗效,但对于保险计划而言,NA治疗费用昂贵:对美国医疗保险与医疗补助服务中心(Centers for Medicare & Medicaid Services)2012 年至 2021 年的数据库进行了评估,以评估医疗补助计划(Medicaid)患者使用 NA 治疗慢性乙型肝炎(CHB)的情况。提取的数据包括按原研药和非专利药分层的每种药物的索赔数量、单位和费用:在研究期间,NA的支出为19亿美元,2016年达到峰值,为2.89亿美元,随后有所下降。2016 年以来支出的减少与仿制药使用的增加有关。在研究期间,使用仿制药替诺福韦或恩替卡韦节省了6.69亿美元:非专利药使用的增加大大降低了NA药物的支出;政策向非专利药使用的转变可能有助于实现可持续性。
{"title":"Spending on nucleos(t)ide analogues for hepatitis B in medicaid beneficiaries: 2012-2021","authors":"Stephen E. Congly ,&nbsp;Mayur Brahmania ,&nbsp;Carla S. Coffin","doi":"10.1016/j.aohep.2024.101509","DOIUrl":"10.1016/j.aohep.2024.101509","url":null,"abstract":"<div><h3>Introduction and Objectives</h3><p>Treatment of chronic hepatitis B (CHB) with nucelos(t)ide analogues (NA) can improve outcomes, but NA treatment is expensive for insurance plans.</p></div><div><h3>Materials and Methods</h3><p>The Centers for Medicare &amp; Medicaid Services database was assessed from 2012 to 2021 to assess the use of NA for CHB in patients on Medicaid. Data extracted included the number of claims, units, and costs of each agent stratified by originator and generic.</p></div><div><h3>Results</h3><p>Over the study period, 1.9 billion USD was spent on NA, with spending peaking in 2016 at $289 million US, which has subsequently decreased. Lower expenditures since 2016 have been associated with increased use of generics. The use of generic tenofovir or entecavir led to savings of $669 million US over the study period.</p></div><div><h3>Conclusions</h3><p>Increased generic use has significantly reduced expenditures for NA drugs; policy shifts towards generic drug use may help with sustainability.</p></div>","PeriodicalId":7979,"journal":{"name":"Annals of hepatology","volume":"29 4","pages":"Article 101509"},"PeriodicalIF":3.8,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S166526812400303X/pdfft?md5=80b949017c82b0852edaae9546714f2f&pid=1-s2.0-S166526812400303X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140856309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Annals of hepatology
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