JHEP Reports最新文献_第7页

Molecular imaging of macrophage composition and dynamics in MASLD MASLD 中巨噬细胞组成和动态的分子成像

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-16 DOI: 10.1016/j.jhepr.2024.101220

Bin Q. Yang , Mandy M. Chan , Gyu Seong Heo , Lanlan Lou , Hannah Luehmann , Christopher Park , Alexandria Li , Divangana Lahad , Deborah Sultan , Peter Voller , Kathleen Byrnes , Christina Fu , Yongjian Liu , Joel D. Schilling

Background & Aims

Metabolic-dysfunction associated steatohepatitis (MASH) is associated with obesity and diabetes, and is linked to liver fibrosis and cardiovascular disease. Identification of patients who have MASH is challenging and the development of non-invasive strategies to diagnose and follow this condition is an important unmet need. Recent studies in mouse and humans have identified that significant changes occur in liver macrophage composition during MASH progression; namely, resident Kupffer cells decrease in number while recruited monocyte-derived macrophages increase.

Methods

We developed peptide radiotracers targeted to C–C motif chemokine receptor 2 (CCR2) and CD163 to conduct positron emission tomography (PET) imaging of recruited vs. resident macrophages, respectively. Mice were placed on a MASH-inducing diet and non-invasive PET imaging of the liver was performed with tissue confirmation studies using flow cytometry and immunofluorescence. Statistical analyses were conducted using Student’s t tests, Pearson correlational analysis, and linear regression.

Results

Using a mouse model of MASH, we found that the liver uptake of both CCR2 and CD163 radiotracers detected an increase in recruited cells and a decrease in resident macrophages. These findings correlated well with tissue macrophage content assessed by flow cytometry with an r value of 0.77 (p = 0.002) and 0.78 (p = 0.001) for CCR2 and CD163, respectively. Serial imaging with these radiotracers at several time points during MASH progression and regression revealed good correlation between liver macrophage composition and PET signal intensity.

Conclusion

We demonstrate that novel PET radiotracers targeting CCR2 and CD163 can be used to image macrophage composition in MASH. Non-invasive molecular imaging of inflammation has the potential for diagnosis and monitoring of disease activity in humans with MASH.

Impact and implications:

Macrophage-mediated inflammation contributes to MASH progression and fibrosis; however, liver biopsy is currently the only tool to assess this response. Thus, the development of non-invasive imaging modalities to identify and follow inflammatory activation is an area of need for patient care. In this study, we leverage molecular imaging using PET radiotracers to follow changes in macrophage composition that are related to MASH disease activity. The results in our preclinical model provide important proof of concept evidence that this approach can be used to diagnose MASH and to follow disease activity in response to intervention. Ongoing studies will evaluate the utility of this modality in humans with MASH.

背景& 目的代谢功能障碍相关性脂肪性肝炎（MASH）与肥胖和糖尿病有关，并与肝纤维化和心血管疾病相关。鉴别 MASH 患者具有挑战性，开发诊断和跟踪该病症的非侵入性策略是一项尚未满足的重要需求。最近在小鼠和人类身上进行的研究发现，在 MASH 进展过程中，肝脏巨噬细胞的组成发生了显著变化；即常驻 Kupffer 细胞数量减少，而招募的单核细胞衍生巨噬细胞数量增加。方法我们开发了针对 C-C motif 趋化因子受体 2 (CCR2) 和 CD163 的多肽放射性racers，分别对招募的巨噬细胞和常驻的巨噬细胞进行正电子发射断层扫描（PET）成像。将小鼠置于 MASH 诱导饮食中，对肝脏进行无创 PET 成像，并使用流式细胞术和免疫荧光进行组织确认研究。结果使用 MASH 小鼠模型，我们发现肝脏对 CCR2 和 CD163 放射性核素的摄取检测到招募细胞的增加和常驻巨噬细胞的减少。这些发现与流式细胞术评估的组织巨噬细胞含量密切相关，CCR2和CD163的r值分别为0.77（p = 0.002）和0.78（p = 0.001）。结论我们证明了靶向 CCR2 和 CD163 的新型 PET 放射性同位素可用于 MASH 中巨噬细胞组成的成像。影响和意义：巨噬细胞介导的炎症导致了 MASH 的进展和纤维化；然而，肝活检是目前评估这种反应的唯一工具。因此，开发无创成像模式来识别和跟踪炎症激活是患者护理的一个需求领域。在这项研究中，我们利用 PET 放射性同位素的分子成像技术来跟踪与 MASH 疾病活动相关的巨噬细胞组成的变化。我们在临床前模型中取得的结果提供了重要的概念验证证据，证明这种方法可用于诊断 MASH 并跟踪疾病活动对干预措施的反应。正在进行的研究将评估这种方法在人类MASH患者中的实用性。

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引用次数: 0

Application of a deep learning algorithm for the diagnosis of HCC 一种深度学习算法在HCC诊断中的应用

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-16 DOI: 10.1016/j.jhepr.2024.101219

Philip Leung Ho Yu , Keith Wan-Hang Chiu , Jianliang Lu , Gilbert C.S. Lui , Jian Zhou , Ho-Ming Cheng , Xianhua Mao , Juan Wu , Xin-Ping Shen , King Ming Kwok , Wai Kuen Kan , Y.C. Ho , Hung Tat Chan , Peng Xiao , Lung-Yi Mak , Vivien W.M. Tsui , Cynthia Hui , Pui Mei Lam , Zijie Deng , Jiaqi Guo , Wai-Kay Seto

Background & Aims

Hepatocellular carcinoma (HCC) is characterized by a high mortality rate. The Liver Imaging Reporting and Data System (LI-RADS) results in a considerable number of indeterminate observations, rendering an accurate diagnosis difficult.

Methods

We developed four deep learning models for diagnosing HCC on computed tomography (CT) via a training–validation–testing approach. Thin-slice triphasic CT liver images and relevant clinical information were collected and processed for deep learning. HCC was diagnosed and verified via a 12-month clinical composite reference standard. CT observations among at-risk patients were annotated using LI-RADS. Diagnostic performance was assessed by internal validation and independent external testing. We conducted sensitivity analyses of different subgroups, deep learning explainability evaluation, and misclassification analysis.

Results

From 2,832 patients and 4,305 CT observations, the best-performing model was Spatio-Temporal 3D Convolution Network (ST3DCN), achieving area under receiver-operating-characteristic curves (AUCs) of 0.919 (95% CI, 0.903–0.935) and 0.901 (95% CI, 0.879–0.924) at the observation (n = 1,077) and patient (n = 685) levels, respectively during internal validation, compared with 0.839 (95% CI, 0.814–0.864) and 0.822 (95% CI, 0.790–0.853), respectively for standard of care radiological interpretation. The negative predictive values of ST3DCN were 0.966 (95% CI, 0.954–0.979) and 0.951 (95% CI, 0.931–0.971), respectively. The observation-level AUCs among at-risk patients, 2–5-cm observations, and singular portovenous phase analysis of ST3DCN were 0.899 (95% CI, 0.874–0.924), 0.872 (95% CI, 0.838–0.909) and 0.912 (95% CI, 0.895–0.929), respectively. In external testing (551/717 patients/observations), the AUC of ST3DCN was 0.901 (95% CI, 0.877–0.924), which was non-inferior to radiological interpretation (AUC 0.900; 95% CI, 0.877–-923).

Conclusions

ST3DCN achieved strong, robust performance for accurate HCC diagnosis on CT. Thus, deep learning can expedite and improve the process of diagnosing HCC.

Impact and implications:

The clinical applicability of deep learning in HCC diagnosis is potentially huge, especially considering the expected increase in the incidence and mortality of HCC worldwide. Early diagnosis through deep learning can lead to earlier definitive management, particularly for at-risk patients. The model can be broadly deployed for patients undergoing a triphasic contrast CT scan of the liver to reduce the currently high mortality rate of HCC.

背景,目的肝细胞癌（HCC）的特点是死亡率高。肝脏成像报告和数据系统（LI-RADS）导致大量不确定的观察结果，使准确诊断变得困难。方法采用训练-验证-测试的方法，建立了4种用于CT诊断HCC的深度学习模型。收集肝脏薄层三相CT图像及相关临床信息进行深度学习处理。通过12个月的临床综合参考标准诊断和证实HCC。高危患者的CT观察使用LI-RADS进行注释。通过内部验证和独立的外部测试来评估诊断性能。我们进行了不同亚组的敏感性分析、深度学习可解释性评估和错误分类分析。结果在2,832例患者和4,305例CT观察中，表现最好的模型是时空三维卷积网络（ST3DCN），在内部验证时，在观察（n = 1,077）和患者（n = 685）水平上，接受者操作特征曲线下面积（auc）分别为0.919 （95% CI, 0.903-0.935）和0.901 (95% CI, 0.879-0.924)，而在内部验证时，前者为0.839 （95% CI, 0.814-0.864）和0.822 （95% CI, 0.790-0.853）。分别为护理标准放射学解释。ST3DCN阴性预测值分别为0.966 （95% CI, 0.954-0.979）和0.951 （95% CI, 0.931-0.971）。高危患者、2 - 5 cm观察和ST3DCN单门静脉相分析的观察水平auc分别为0.899 （95% CI, 0.874-0.924）、0.872 （95% CI, 0.838-0.909）和0.912 （95% CI, 0.895-0.929）。在外部检测（551/717例患者/观察）中，ST3DCN的AUC为0.901 (95% CI, 0.877-0.924)，不低于放射学解释(AUC 0.900；95% ci, 0.877—923)。结论st3dcn对肝癌的CT准确诊断具有较强的稳健性。因此，深度学习可以加快和改善HCC的诊断过程。影响和启示：深度学习在HCC诊断中的临床应用潜力巨大，特别是考虑到全球HCC发病率和死亡率的预期增长。通过深度学习进行早期诊断可以实现更早的明确管理，特别是对高危患者。该模型可广泛应用于肝脏CT三相对比扫描患者，以降低目前HCC的高死亡率。

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引用次数: 0

ALDH1L2 drives HCC progression through TAM polarization ALDH1L2通过TAM极化驱动HCC进展

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-12 DOI: 10.1016/j.jhepr.2024.101217

Jiajun Li , Chi Zhang , Qingqing Zhou , Qinqin Long , Jiayi Chen , Lili Meng , Wei Tian , Yue Yang , Chao Ge , Yuting Su , Xi-Dai Long , Jun Wu , Hua Tian

Background & Aims

Dysregulation of one-carbon metabolism is considered an early hallmark of mitochondrial dysfunction and cancer metabolism. ALDH1L2 belongs to the aldehyde dehydrogenase family and plays an important role in tumor progression. However, little is known about the precise role and underlying mechanisms of ALDH1L2 in hepatocellular carcinoma (HCC).

Methods

Immunohistochemistry, western blotting, and immunofluorescence staining were used to evaluate ALDH1L2 expression in HCC samples (n = 90) and cell lines (n = 9). A series of in vitro and in vivo assays were performed to explore the role and molecular mechanism of ALDH1L2 in HCC progression.

Results

ALDH1L2 upregulation is associated with poor prognosis in HCC (hazard ratio 1.923; 95% confidence interval 1.03–3.59; p = 0.04). ALDH1L2 promotes tumor cell proliferation and metastasis by activating NRF2/IL-6/STAT3 signaling. ALDH1L2 promotes mitochondrial respiration, increases ATP production and protects HCC cells from reactive oxygen species-induced cellular damage via NRF2 stabilization. NRF2 also directly binds to the ALDH1L2 promoter and increases ALDH1L2 transcription, thereby establishing a positive feedback loop to maintain the function of ALDH1L2. The interaction between tumor-associated macrophages and ALDH1L2-overexpressing HCC cells further promotes HCC progression. In addition, ALDH1L2 knockdown enhances the anti-HCC activity of the tyrosine kinase inhibitor sorafenib.

Conclusions

These findings provide the first evidence indicating that ALDH1L2 is directly involved in tumor progression by interacting with tumor-associated macrophages through the Jak2/STAT3 signaling pathway and that ALDH1L2 may be a target molecule for HCC therapy.

Impact and implications:

This research highlights that ALDH1L2 could serve as a predictive and prognostic marker in HCC. We found that a positive feedback loop between ALDH1L2 and NRF2 promotes HCC progression by activating the IL-6/Jak2/STAT3 signaling axis and tumor-associated macrophage polarization. In addition, we found that ALDH1L2 knockdown enhances the anti-HCC effect of sorafenib.

背景,目的单碳代谢失调被认为是线粒体功能障碍和癌症代谢的早期标志。ALDH1L2属于醛脱氢酶家族，在肿瘤进展中起重要作用。然而，ALDH1L2在肝细胞癌（HCC）中的确切作用和潜在机制尚不清楚。方法采用免疫组化、免疫印迹和免疫荧光染色法检测90例HCC标本和9例肝癌细胞系中ALDH1L2的表达，并进行一系列体内外实验，探讨ALDH1L2在HCC进展中的作用及其分子机制。结果saldh1l2表达上调与HCC预后不良相关(危险比1.923；95%置信区间1.03-3.59；P = 0.04)。ALDH1L2通过激活NRF2/IL-6/STAT3信号通路促进肿瘤细胞增殖和转移。ALDH1L2促进线粒体呼吸，增加ATP的产生，并通过NRF2稳定保护HCC细胞免受活性氧诱导的细胞损伤。NRF2也直接结合ALDH1L2启动子，增加ALDH1L2的转录，从而建立一个正反馈回路，维持ALDH1L2的功能。肿瘤相关巨噬细胞与过表达aldh1l2的HCC细胞之间的相互作用进一步促进了HCC的进展。此外，ALDH1L2敲低可增强酪氨酸激酶抑制剂索拉非尼的抗hcc活性。这些发现首次证明ALDH1L2通过Jak2/STAT3信号通路与肿瘤相关巨噬细胞相互作用，直接参与肿瘤进展，ALDH1L2可能是HCC治疗的靶分子。影响和意义：本研究强调ALDH1L2可以作为HCC的预测和预后指标。我们发现ALDH1L2和NRF2之间的正反馈回路通过激活IL-6/Jak2/STAT3信号轴和肿瘤相关的巨噬细胞极化来促进HCC进展。此外，我们发现ALDH1L2敲低可增强索拉非尼的抗hcc作用。

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引用次数: 0

Microcystin-RR is a biliary toxin selective for neonatal extrahepatic cholangiocytes 微囊藻毒素是新生儿肝外胆管细胞选择性胆道毒素

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-12 DOI: 10.1016/j.jhepr.2024.101218

Kapish Gupta , Dongning Chen , Rebecca G. Wells

Background & Aims

Biliary atresia is a fibrosing cholangiopathy affecting neonates that is thought to result from a prenatal environmental insult to the bile duct. Biliatresone, a plant toxin with an α-methylene ketone group, was previously implicated in biliary atresia in Australian livestock, but is found in a limited location and is unlikely to be a significant human toxin. We hypothesized that other unsaturated carbonyl compounds, some with the potential for significant human exposure, might also be biliary toxins.

Methods

We focused on the family of microcystins, cyclic peptide toxins from blue-green algae that are found worldwide, particularly during harmful algal blooms. We used primary extrahepatic cholangiocyte spheroids and extrahepatic bile duct explants from both neonatal [a total of 86 postnatal day (P) 2 mouse pups and 18 P2 rat pups (n = 8–10 per condition for both species)] and adult rodents [a total of 31 P15–18 mice (n = 10 or 11 per condition)] to study the biliary toxicity of microcystins and potential mechanisms involved.

Results

Results showed that 400 nM microcystin (MC)-RR, but not six other microcystins or the related algal toxin nodularin, caused >80% lumen closure in cell spheroids made from extrahepatic cholangiocytes isolated from 2–3-day-old mice (p <0.0001). By contrast, 400 nM MC-RR resulted in less than an average 5% lumen closure in spheroids derived from neonatal intrahepatic cholangiocytes or cells from adult mice (p = 0.4366). In addition, MC-RR caused occlusion of extrahepatic bile duct explants from 2-day-old mice (p <0.0001), but not 18-day-old mice. MC-RR also caused a 2.3-times increase in reactive oxygen species in neonatal cholangiocytes (p <0.0001), and treatment with N-acetyl cysteine partially prevented microcystin-RR-induced lumen closure (p = 0.0004), suggesting a role for redox homeostasis in its mechanism of action.

Conclusions

We identified MC-RR as a selective neonatal extrahepatic cholangiocyte toxin and suggest that it acts by increasing redox stress.

Impact and implications:

The plant toxin biliatresone causes a biliary atresia-like disease in livestock and vertebrate animal model systems. We tested the widespread blue-green algal toxin, microcystin-RR, another highly electrophilic unsaturated carbonyl compound that is released during harmful algal blooms, and found that it was also a biliary toxin with specificity for neonatal extrahepatic cholangiocytes. This work should drive further animal studies and, ultimately, studies to determine whether human exposure to microcystin-RR causes biliary atresia.

背景,目的胆道闭锁是一种影响新生儿的纤维化胆管疾病，被认为是由产前胆管环境损伤引起的。胆管松是一种含有α-亚甲基酮的植物毒素，以前曾在澳大利亚牲畜的胆道闭锁中发现，但在有限的地方发现，不太可能是一种重要的人类毒素。我们假设其他不饱和羰基化合物，其中一些可能对人类有重大影响，也可能是胆道毒素。方法研究了微囊藻毒素家族，这是一种来自世界各地，特别是在有害藻华期间发现的蓝绿藻的环肽毒素。我们使用原代肝外胆管细胞球状体和肝外胆管外植体，分别来自新生儿[共86只出生后2天(P)小鼠幼崽和18只P2大鼠幼崽（每种情况n = 8-10只）]和成年啮齿动物[共31只P15-18小鼠（每种情况n = 10或11只）]，研究微囊藻毒素的胆道毒性及其可能的机制。结果表明，400 nM微囊藻毒素(MC)-RR可导致2 - 3日龄小鼠肝外胆管细胞80%的管腔闭合（p <0.0001），而其他6种微囊藻毒素或相关藻毒素结节素则没有作用。相比之下，400 nM MC-RR导致来自新生儿肝内胆管细胞或成年小鼠细胞的球体的管腔关闭率低于平均5% （p = 0.4366）。此外，MC-RR导致2日龄小鼠肝外胆管移植体闭塞（p <0.0001），但18日龄小鼠没有。MC-RR还导致新生儿胆管细胞中活性氧增加2.3倍（p <0.0001），并且n-乙酰半胱氨酸治疗部分阻止了微囊藻素- rr诱导的管腔闭合（p = 0.0004），提示其作用机制可能与氧化还原稳态有关。我们发现MC-RR是一种选择性的新生儿肝外胆管细胞毒素，并认为它通过增加氧化还原应激起作用。影响和启示：植物毒素胆甾醇在家畜和脊椎动物模型系统中引起胆道闭锁样疾病。我们测试了广泛存在的蓝绿藻毒素微囊藻毒素- rr，这是另一种在有害藻华期间释放的高度亲电的不饱和羰基化合物，发现它也是一种对新生儿肝外胆管细胞具有特异性的胆道毒素。这项工作将推动进一步的动物研究，并最终确定人类暴露于微囊藻毒素- rr是否会导致胆道闭锁。

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引用次数: 0

Virological markers for clinical trials in chronic viral hepatitis 慢性病毒性肝炎临床试验的病毒学标志物

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-07 DOI: 10.1016/j.jhepr.2024.101214

Jean-Michel Pawlotsky

Chronic hepatitis virus infections remain a major public health problem, despite significant therapeutic advances over the past two decades. Considerable progress has been made in the treatment of chronic viral hepatitis, but continued efforts are needed to develop and bring to market new drugs to fill the gaps in the current therapeutic armamentarium. Thus, clinical trials to assess the safety and efficacy of these new therapeutic approaches, including the selection of reliable and objective treatment endpoints, are still needed. Virological biomarkers play an important role in the diagnosis, monitoring, and evaluation of antiviral treatment efficacy. They are often used as primary or secondary endpoints in the evaluation of new treatments for chronic viral hepatitis. However, these markers are not all equally informative. The aim of this review article is to provide a comprehensive overview of the available virological tests for chronic viral hepatitis due to hepatitis B, D, C and E viruses, the information they provide and lack, the specific challenges associated with each, and their use in clinical trials of new treatments.

尽管过去二十年在治疗方面取得了重大进展，但慢性肝炎病毒感染仍然是一个重大的公共卫生问题。慢性病毒性肝炎的治疗已经取得了相当大的进展，但仍需继续努力开发新药并将其推向市场，以填补目前治疗手段的空白。因此，仍需要进行临床试验来评估这些新治疗方法的安全性和有效性，包括选择可靠、客观的治疗终点。病毒学生物标志物在诊断、监测和评估抗病毒治疗效果方面发挥着重要作用。在评估慢性病毒性肝炎的新疗法时，它们通常被用作主要或次要终点。然而，这些标记物的信息量并不都一样。本综述文章旨在全面概述乙型、丁型、丙型和戊型肝炎病毒引起的慢性病毒性肝炎的现有病毒学检测方法、它们提供和缺乏的信息、与每种检测方法相关的具体挑战以及它们在新疗法临床试验中的应用。

引用次数: 0

Oncogenic role of PMEPA1 and its association with immune exhaustion and TGF-β activation in HCC PMEPA1 的致癌作用及其与 HCC 中免疫衰竭和 TGF-β 激活的关系

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-07 DOI: 10.1016/j.jhepr.2024.101212

Marta Piqué-Gili , Carmen Andreu-Oller , Agavni Mesropian , Roger Esteban-Fabró , Marina Bárcena-Varela , Marina Ruiz de Galarreta , Carla Montironi , Iris Martinez-Quetglas , Sarah Cappuyns , Judit Peix , Ieva Keraite , Albert Gris-Oliver , Elisa Fernández-Martínez , Ezequiel Mauro , Miguel Torres-Martin , Jordi Abril-Fornaguera , Katherine E. Lindblad , Diether Lambrechts , Jeroen Dekervel , Swan N. Thung , Josep M. Llovet

<div><h3>Background & Aims</h3><div>Transforming growth factor β (TGF-β) plays an oncogenic role in advanced cancer by promoting cell proliferation, metastasis and immunosuppression. <em>PMEPA1</em> (prostate transmembrane protein androgen induced 1) has been shown to promote TGF-β oncogenic effects in other tumour types. Thus, we aimed to explore the role of <em>PMEPA1</em> in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>We analysed 1,097 tumours from patients with HCC, including discovery (n = 228) and validation (n = 361) cohorts with genomic and clinicopathological data. <em>PMEPA1</em> levels were assessed by qPCR (n = 228), gene expression data (n = 869) and at the single-cell level (n = 54). Genetically engineered mouse models overexpressing <em>MYC+PMEPA1</em> compared to <em>MYC</em> were generated and molecular analyses were performed on the HCCs obtained.</div></div><div><h3>Results</h3><div><em>PMEPA1</em> was overexpressed in 18% of HCC samples (fold-change >2; n = 201/1,097), a feature associated with TGF-β signalling activation (<em>p <</em>0.05) and absence of gene body hypomethylation (<em>p <</em>0.01). HCCs showing both TGF-β signalling and high <em>PMEPA1</em> levels (12% of cases) were linked to immune exhaustion, late TGF-β activation, aggressiveness and higher recurrence rates after resection, in contrast to HCCs with only TGF-β signalling (8%) or <em>PMEPA1</em> overexpression (9%). Single-cell RNA sequencing analysis identified <em>PMEPA1</em> expression in HCC and stromal cells. <em>PMEPA1</em>-expressing tumoural cells were predicted to interact with CD4<sup>+</sup> regulatory T cells and CD4<sup>+</sup> CXCL13<sup>+</sup> and CD8<sup>+</sup> exhausted T cells. <em>In vivo</em>, overexpression of <em>MYC</em>+<em>PMEPA1</em> led to HCC development in ∼60% of mice and a decreased survival compared to mice overexpressing <em>MYC</em> alone (<em>p =</em> 0.014). <em>MYC</em>+<em>PMEPA1</em> tumours were enriched in TGF-β signalling, paralleling our human data.</div></div><div><h3>Conclusions</h3><div>In human HCC, <em>PMEPA1</em> upregulation is linked to TGF-β activation, immune exhaustion, and an aggressive phenotype. Overexpression of <em>PMEPA1+MYC</em> led to tumoural development <em>in vivo</em>, demonstrating the oncogenic role of <em>PMEPA1</em> in HCC for the first time.</div></div><div><h3>Impact and implications:</h3><div><em>PMEPA1</em> can enhance the tumour-promoting effects of TGF-β in cancer. In this study, we demonstrate that <em>PMEPA1</em> is highly expressed in ∼18% of patients with hepatocellular carcinoma (HCC), a feature associated with poor prognosis, TGF-β activation and exhaustion of immune cells. Similarly, in mouse models, <em>PMEPA1</em> overexpression promotes HCC development, which demonstrates its oncogenic role. The identification of <em>PMEPA1</em> as oncogenic driver in HCC and its role in immune exhaustion and poor clinical outcomes enhances our under

背景& 目的转化生长因子 β（TGF-β）通过促进细胞增殖、转移和免疫抑制，在晚期癌症中发挥致癌作用。在其他肿瘤类型中，PMEPA1（前列腺跨膜蛋白雄激素诱导 1）已被证明可促进 TGF-β 的致癌作用。因此，我们旨在探索PMEPA1在肝细胞癌（HCC）中的作用。方法我们分析了1,097例HCC患者的肿瘤，包括发现组（n = 228）和验证组（n = 361）的基因组和临床病理数据。通过 qPCR（n = 228）、基因表达数据（n = 869）和单细胞水平（n = 54）评估 PMEPA1 水平。结果PMEPA1在18%的HCC样本中过表达（折叠变化>2; n = 201/1,097），这一特征与TGF-β信号激活（p <0.05）和基因体低甲基化缺失（p <0.01）有关。同时显示 TGF-β 信号和高 PMEPA1 水平的 HCC（12% 的病例）与免疫衰竭、晚期 TGF-β 激活、侵袭性和切除后较高的复发率有关，而仅显示 TGF-β 信号的 HCC（8%）或 PMEPA1 过表达的 HCC（9%）则与之相反。单细胞RNA测序分析确定了PMEPA1在HCC和基质细胞中的表达。据预测，表达PMEPA1的肿瘤细胞会与CD4+调节性T细胞、CD4+ CXCL13+和CD8+衰竭性T细胞相互作用。在体内，与单独过表达 MYC 的小鼠相比，过表达 MYC+PMEPA1 会导致 60% 的小鼠发生 HCC 并降低存活率（p = 0.014）。结论在人类 HCC 中，PMEPA1 的上调与 TGF-β 激活、免疫耗竭和侵袭性表型有关。PMEPA1+MYC的过表达导致体内肿瘤发生，首次证明了PMEPA1在HCC中的致癌作用。本研究表明，PMEPA1在18%的肝细胞癌（HCC）患者中高表达，这一特征与预后不良、TGF-β激活和免疫细胞衰竭有关。同样，在小鼠模型中，PMEPA1 的过表达会促进 HCC 的发展，这表明了它的致癌作用。PMEPA1是HCC的致癌驱动因子，它在免疫耗竭和不良临床预后中的作用加深了我们对HCC发病机制的了解，为靶向治疗干预开辟了新途径。

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引用次数: 0

Liver stiffness measurement predicts clinical outcomes in autoimmune hepatitis 肝脏硬度测量可预测自身免疫性肝炎的临床结果

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-06 DOI: 10.1016/j.jhepr.2024.101213

Ignasi Olivas , Pinelopi Arvaniti , Stella Gabeta , Sonia Torres , Maria Del Barrio , Alvaro Díaz-González , Paula Esteban , Mar Riveiro-Barciela , Ezequiel Mauro , Sergio Rodríguez-Tajes , Kalliopi Zachou , George N. Dalekos , María-Carlota Londoño

Background & Aims

Liver stiffness measurement (LSM) has been shown to adequately predict outcomes in patients with liver disease. However, the value of LSM as a predictor of disease progression in autoimmune hepatitis (AIH) remains to be determined. This study aimed to evaluate the role of LSM as a predictor of disease progression and decompensation of cirrhosis in patients with AIH.

Methods

This multicentre cohort study included 439 patients with histologically confirmed AIH and at least one LSM during follow-up. The association between the first LSM performed at least 6 months after treatment initiation (baseline LSM [BLSM]) and cirrhosis development and poor outcomes (decompensation, liver transplantation, and/or liver-related death) was assessed using Cox regression and its discriminating capacity with a receiver-operating characteristic curve.

Results

Most patients were female (n = 301, 70%), with a median age of 52 years. BLSM performed after a median of 2.18 (1.19-4.68) years had a median value of 6 kPa (4.5-8.5). At the time of BLSM, 332 (76%) patients had achieved a biochemical response and 57 (13%) had cirrhosis. During follow-up, eight patients (2%) presented with poor outcomes and 26 (7%) developed cirrhosis. BLSM was higher among patients with poor outcomes (13.5 kPa vs. 6 kPa; p <0.001) and was independently associated with cirrhosis development (hazard ratio 1.300; p <0.001), irrespective of the achievement of biochemical response. A cut-off of 8.5 kPa accurately predicted cirrhosis development and poor outcomes, with AUCs of 0.859 (95% CI 0.789-0.929) and 0.900 (95% CI 0.847-0.954), respectively.

Conclusion

BLSM could play a significant role in predicting AIH outcomes, potentially identifying a subgroup of patients at a high risk of progressing to cirrhosis and experiencing decompensation.

Impact and implications:

The value of liver stiffness measurement as a predictor of outcomes in patients with autoimmune hepatitis (AIH) remains to be determined. In this large multicentre study, liver stiffness measurement was found to be an independent predictive factor of adverse clinical outcomes and cirrhosis development in AIH, irrespective of the achievement of biochemical response. A cut-off of 8.5 kPa accurately predicted cirrhosis development and poor outcomes in AIH.

背景& 目的肝脏僵硬度测量（LSM）已被证明能充分预测肝病患者的预后。然而，肝硬度测量作为自身免疫性肝炎（AIH）疾病进展预测指标的价值仍有待确定。本研究旨在评估 LSM 作为自身免疫性肝炎患者疾病进展和肝硬化失代偿的预测指标的作用。方法这项多中心队列研究纳入了 439 例经组织学确诊的自身免疫性肝炎患者，这些患者在随访期间至少接受过一次 LSM 检查。结果大多数患者为女性（n = 301，70%），中位年龄为 52 岁。在中位 2.18（1.19-4.68）年后进行的 BLSM 的中位值为 6 kPa（4.5-8.5）。在进行 BLSM 时，有 332 名（76%）患者获得了生化应答，57 名（13%）患者出现了肝硬化。在随访期间，8 名患者（2%）出现不良反应，26 名患者（7%）发展为肝硬化。无论是否获得生化应答，预后不良患者的 BLSM 均较高（13.5 kPa vs. 6 kPa; p <0.001），并且与肝硬化的发展独立相关（危险比 1.300; p <0.001）。8.5 kPa 临界值可准确预测肝硬化的发展和不良预后，其 AUC 分别为 0.859 (95% CI 0.789-0.929) 和 0.900 (95% CI 0.847-0.954)。影响和意义：肝脏硬度测量作为自身免疫性肝炎（AIH）患者预后预测指标的价值仍有待确定。在这项大型多中心研究中发现，肝脏僵硬度测量是自身免疫性肝炎患者不良临床结局和肝硬化发展的独立预测因素，与生化反应的实现无关。8.5 kPa的临界值可准确预测AIH患者肝硬化的发生和不良预后。

{"title":"Liver stiffness measurement predicts clinical outcomes in autoimmune hepatitis","authors":"Ignasi Olivas , Pinelopi Arvaniti , Stella Gabeta , Sonia Torres , Maria Del Barrio , Alvaro Díaz-González , Paula Esteban , Mar Riveiro-Barciela , Ezequiel Mauro , Sergio Rodríguez-Tajes , Kalliopi Zachou , George N. Dalekos , María-Carlota Londoño","doi":"10.1016/j.jhepr.2024.101213","DOIUrl":"10.1016/j.jhepr.2024.101213","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Liver stiffness measurement (LSM) has been shown to adequately predict outcomes in patients with liver disease. However, the value of LSM as a predictor of disease progression in autoimmune hepatitis (AIH) remains to be determined. This study aimed to evaluate the role of LSM as a predictor of disease progression and decompensation of cirrhosis in patients with AIH.</div></div><div><h3>Methods</h3><div>This multicentre cohort study included 439 patients with histologically confirmed AIH and at least one LSM during follow-up. The association between the first LSM performed at least 6 months after treatment initiation (baseline LSM [BLSM]) and cirrhosis development and poor outcomes (decompensation, liver transplantation, and/or liver-related death) was assessed using Cox regression and its discriminating capacity with a receiver-operating characteristic curve.</div></div><div><h3>Results</h3><div>Most patients were female (n = 301, 70%), with a median age of 52 years. BLSM performed after a median of 2.18 (1.19-4.68) years had a median value of 6 kPa (4.5-8.5). At the time of BLSM, 332 (76%) patients had achieved a biochemical response and 57 (13%) had cirrhosis. During follow-up, eight patients (2%) presented with poor outcomes and 26 (7%) developed cirrhosis. BLSM was higher among patients with poor outcomes (13.5 kPa <em>vs.</em> 6 kPa; <em>p <</em>0.001) and was independently associated with cirrhosis development (hazard ratio 1.300; <em>p <</em>0.001), irrespective of the achievement of biochemical response. A cut-off of 8.5 kPa accurately predicted cirrhosis development and poor outcomes, with AUCs of 0.859 (95% CI 0.789-0.929) and 0.900 (95% CI 0.847-0.954), respectively.</div></div><div><h3>Conclusion</h3><div>BLSM could play a significant role in predicting AIH outcomes, potentially identifying a subgroup of patients at a high risk of progressing to cirrhosis and experiencing decompensation.</div></div><div><h3>Impact and implications:</h3><div>The value of liver stiffness measurement as a predictor of outcomes in patients with autoimmune hepatitis (AIH) remains to be determined. In this large multicentre study, liver stiffness measurement was found to be an independent predictive factor of adverse clinical outcomes and cirrhosis development in AIH, irrespective of the achievement of biochemical response. A cut-off of 8.5 kPa accurately predicted cirrhosis development and poor outcomes in AIH.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101213"},"PeriodicalIF":9.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142539624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

A home-based exercise programme attenuates fatigue in primary biliary cholangitis: Results from the EXCITED clinical trial 家庭锻炼计划可减轻原发性胆汁性胆管炎患者的疲劳感：EXCITED 临床试验的结果

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-06 DOI: 10.1016/j.jhepr.2024.101210

Alice Freer , Felicity R. Williams , Simon Durman , Jennifer Hayden , Matthew J. Armstrong , Palak J. Trivedi

Background & Aims

Fatigue is a commonly reported symptom of primary biliary cholangitis (PBC). We conducted a single-arm, open-label clinical trial to assess the efficacy of a physiotherapist-led home-based exercise programme (HBEP) in patients with PBC and moderate-to-severe fatigue (NCT04265235).

Methods

A 12-week individualised HBEP (aerobic + resistance based) was delivered to patients with a PBC-40 fatigue domain score ≥33. The primary efficacy outcome measure was a reduction in fatigue severity by ≥5 points. Secondary outcome measures included other domains of PBC-40, the FIS (fatigue impact scale), ESS (Epworth sleepiness score), HADS (hospital anxiety and depression scale), aerobic capacity (ISWT [incremental shuttle walk test], Duke activity status index (predicted VO₂ peak) and physical function (short physical performance battery [SPPB]).

Results

A total of 31 patients were recruited, of whom 30 completed the 12-week HBEP (29 women; median age 53 years, median alkaline phosphatase value: 1.5x the upper limit of normal, median bilirubin: 12 μmol/L, and median baseline PBC-40 fatigue score 42). The primary outcome was met by 26 patients, with a median reduction in PBC-40 fatigue score of -10.5 points (IQR -9 to -13; p <0.001). Reductions were also observed in the symptom, cognition, and emotion domains of PBC-40, and in the FIS, ESS and HADS (p <0.01 for all measures). This was alongside increases in the median ISWT (+90 m; IQR 57.5-110), predicted VO₂ peak (+2.41 ml/kg/min; IQR 0.01-4.05), and SPPB (+1 point; IQR 0-1.4) (all p <0.001). 28 participants achieved the maximum SPPB score of 12/12 (vs. 13 patients at baseline; p <0.001). No significant adverse events were reported.

Conclusion

This proof-of-concept study shows that a HBEP is safe, feasible, and has the potential to attenuate fatigue. Controlled trials are needed to validate the efficacy of exercise interventions in PBC.

Impact and implications:

Fatigue is a common symptom in primary biliary cholangitis (PBC), and is linked to cognitive dysfunction, somnolence, and reduced activity. The pathogenesis is multifactorial, and muscle bioenergetic abnormalities have been proposed to contribute. In this study, we show that a home-based exercise programme, consisting of aerobic and resistance-based sets, can be safely delivered to people living with PBC. In addition, the programme led to a reduction in fatigue severity, less daytime sleepiness and improved cognitive function.

背景& 目的疲劳是原发性胆汁性胆管炎（PBC）的常见症状。我们开展了一项单臂、开放标签临床试验，以评估物理治疗师指导的家庭锻炼计划（HBEP）对中度至重度疲劳的 PBC 患者的疗效（NCT04265235）。主要疗效指标是疲劳严重程度降低≥5分。次要疗效指标包括 PBC-40 的其他领域、FIS（疲劳影响量表）、ESS（埃普沃斯嗜睡评分）、HADS（医院焦虑抑郁量表）、有氧能力（ISWT[增量穿梭步行测试]、杜克活动状态指数（预测 VO₂峰值））和身体功能（短期体能测试 [SPPB]）。结果共招募了 31 名患者，其中 30 人完成了为期 12 周的 HBEP（29 名女性；中位年龄 53 岁，中位碱性磷酸酶值：正常值上限的 1.5 倍，中位胆红素：12 μmol/L，中位 PBC-40 疲劳基线评分 42 分）。26名患者达到了主要疗效，PBC-40疲劳评分的中位数降低了-10.5分（IQR-9至-13；p<0.001）。在 PBC-40 的症状、认知和情绪领域，以及 FIS、ESS 和 HADS 中也观察到了减少（所有测量的 p 均为 0.01）。同时，ISWT 中位数（+90 米；IQR 57.5-110）、预测 VO₂峰值（+2.41 毫升/千克/分钟；IQR 0.01-4.05）和 SPPB（+1 分；IQR 0-1.4）也有所提高（均为 p <0.001）。28 名参与者的 SPPB 最高分达到了 12/12（与基线时的 13 名患者相比；p <0.001）。结论这项概念验证研究表明，HBEP 是安全、可行的，并有可能减轻疲劳。影响和意义：疲劳是原发性胆汁性胆管炎（PBC）的常见症状，与认知功能障碍、嗜睡和活动减少有关。其发病机制是多因素的，肌肉生物能异常被认为是其中的一个因素。在这项研究中，我们发现可以安全地为胆汁淤积症患者提供由有氧运动和阻力运动组成的家庭锻炼计划。此外，该计划还能减轻疲劳的严重程度，减少白天嗜睡，改善认知功能。

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引用次数: 0

Use of artificial intelligence for liver diseases: A survey from the EASL congress 2024 人工智能在肝脏疾病中的应用：2024 年 EASL 大会调查报告

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-06 DOI: 10.1016/j.jhepr.2024.101209

Laura Žigutytė , Thomas Sorz-Nechay , Jan Clusmann , Jakob Nikolas Kather

Artificial intelligence (AI) methods enable humans to analyse large amounts of data, which would otherwise not be feasibly quantifiable. This is especially true for unstructured visual and textual data, which can contain invaluable insights into disease. The hepatology research landscape is complex and has generated large amounts of data to be mined. Many open questions can potentially be addressed with existing data through AI methods. However, the field of AI is sometimes obscured by hype cycles and imprecise terminologies. This can conceal the fact that numerous hepatology research groups already use AI methods in their scientific studies. In this review article, we aim to assess the contemporaneous use of AI methods in hepatology in Europe. To achieve this, we systematically surveyed all scientific contributions presented at the EASL Congress 2024. Out of 1,857 accepted abstracts (1,712 posters and 145 oral presentations), 6 presentations (∼4%) and 69 posters (∼4%) utilised AI methods. Of these, 55 posters were included in this review, while the others were excluded due to missing posters or incomplete methodologies. Finally, we summarise current academic trends in the use of AI methods and outline future directions, providing guidance for scientific stakeholders in the field of hepatology.

人工智能（AI）方法使人类能够分析大量数据，否则这些数据是无法量化的。这对于非结构化的视觉和文本数据来说尤其如此，因为这些数据可能包含对疾病的宝贵见解。肝病学研究领域十分复杂，产生了大量有待挖掘的数据。通过人工智能方法，可以利用现有数据解决许多开放性问题。然而，人工智能领域有时会被炒作周期和不精确的术语所掩盖。这可能掩盖了一个事实，即许多肝病研究小组已经在其科学研究中使用了人工智能方法。在这篇综述文章中，我们旨在评估人工智能方法在欧洲肝病学领域的使用情况。为此，我们系统地调查了在 2024 年 EASL 大会上发表的所有科学论文。在1,857份被接受的摘要（1,712份海报和145份口头报告）中，6份报告（∼4%）和69份海报（∼4%）使用了人工智能方法。其中，55 篇海报被纳入本综述，其他海报因缺失或方法不完整而被排除在外。最后，我们总结了当前使用人工智能方法的学术趋势，并概述了未来的发展方向，为肝病学领域的科研相关人员提供指导。

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引用次数: 0

Metabolomic profiles differentiate between porto-sinusoidal vascular disorder, cirrhosis, and healthy individuals 代谢组图谱区分门静脉血管疾病、肝硬化和健康人

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-09-04 DOI: 10.1016/j.jhepr.2024.101208

Georg Semmler , Oleksandr Petrenko , Juanjo Jose Lozano , Sarah Shalaby , Juan I. Sánchez-Avila , Nara Marella , Thomas Hannich , Katharina Wöran , Lorenz Balcar , Benedikt Simbrunner , Katharina Lampichler , Behrang Mozayani , Michael Trauner , Mattias Mandorfer , Thomas Reiberger , Juan-Carlos García-Pagán , Bernhard Scheiner

Background & Aims

Porto-sinusoidal vascular disorder (PSVD) is a rare and diagnostically challenging vascular liver disease. This study aimed to identify distinct metabolomic signatures in patients with PSVD or cirrhosis to facilitate non-invasive diagnosis and elucidate perturbed metabolic pathways.

Methods

Serum samples from 20 healthy volunteers (HVs), 20 patients with histologically confirmed PSVD or 20 patients with cirrhosis were analyzed. Metabolites were measured using liquid chromatography-mass spectrometry. Differential abundance was evaluated with Limma’s moderated t-statistics. Artificial neural network and support vector machine models were developed to classify PSVD against cirrhosis or HV metabolomic profiles. An independent cohort was used for validation.

Results

A total of 283 metabolites were included for downstream analysis. Clustering effectively separated PSVD from HV metabolomes, although a subset of patients with PSVD (n = 5, 25%) overlapped with those with cirrhosis. Differential testing revealed significant PSVD-linked metabolic perturbations, including pertubations in taurocholic and adipic acids, distinguishing patients with PSVD from both HVs and those with cirrhosis. Alterations in pyrimidine, glycine, serine, and threonine pathways were exclusively associated with PSVD. Machine learning models utilizing selected metabolic signatures reliably differentiated the PSVD group from HVs or patients with cirrhosis using only 4 to 6 metabolites. Validation in an independent cohort demonstrated the high discriminative ability of taurocholic acid (AUROC 0.899) for patients with PSVD vs. HVs and the taurocholic acid/aspartic acid ratio (AUROC 0.720) for PSVD vs. cirrhosis.

Conclusions

High-throughput metabolomics enabled the identification of distinct metabolic profiles that differentiate between PSVD, cirrhosis, and healthy individuals. Unique alterations in the glycine, serine, and threonine pathways suggest their potential involvement in PSVD pathogenesis.

Impact and implications:

Porto-sinusoidal vascular disorder (PSVD) is a vascular liver disease that can lead to pre-sinusoidal portal hypertension in the absence of cirrhosis, with poorly understood pathophysiology and no established treatment. Our study demonstrates that analyzing the serum metabolome could reveal distinct metabolic signatures in patients with PSVD, including alterations in the pyrimidine, glycine, serine and threonine pathways, potentially shedding light on the disease's underlying pathways. These findings could enable earlier and non-invasive diagnosis of PSVD, potentially reducing reliance on invasive procedures like liver biopsy and guiding diagnostic pathways.

背景& 目的门静脉血管病变（PSVD）是一种罕见的血管性肝病，在诊断上具有挑战性。本研究旨在确定PSVD或肝硬化患者独特的代谢组学特征，以促进无创诊断并阐明受干扰的代谢途径。方法分析了20名健康志愿者（HVs）、20名经组织学证实的PSVD患者或20名肝硬化患者的血清样本。代谢物采用液相色谱-质谱法进行测定。差异丰度用 Limma 修正的 t 统计量进行评估。研究人员开发了人工神经网络和支持向量机模型，将 PSVD 与肝硬化或 HV 代谢组学特征进行分类。结果共有283个代谢物被纳入下游分析。聚类分析有效地将 PSVD 与 HV 代谢组分开，尽管 PSVD 患者（5 人，25%）与肝硬化患者重叠。差异检验发现了与 PSVD 相关的重大代谢紊乱，包括牛磺胆酸和脂肪酸的中枢变化，从而将 PSVD 患者与 HV 和肝硬化患者区分开来。嘧啶、甘氨酸、丝氨酸和苏氨酸通路的改变与 PSVD 完全相关。利用精选代谢特征的机器学习模型只需使用 4 到 6 个代谢物就能可靠地将 PSVD 组与 HV 或肝硬化患者区分开来。在一个独立队列中进行的验证表明，牛磺胆酸（AUROC 0.899）对 PSVD 患者与 HVs 具有很高的区分能力，牛磺胆酸/天冬氨酸比值（AUROC 0.720）对 PSVD 与肝硬化具有很高的区分能力。影响和意义：门静脉血管病变（PSVD）是一种血管性肝病，可在无肝硬化的情况下导致门静脉前高压，其病理生理学尚不清楚，也没有成熟的治疗方法。我们的研究表明，分析血清代谢组可以发现 PSVD 患者的不同代谢特征，包括嘧啶、甘氨酸、丝氨酸和苏氨酸通路的改变，从而揭示该疾病的潜在通路。这些发现可以让人们更早地对 PSVD 进行非侵入性诊断，从而减少对肝活检等侵入性程序的依赖，并为诊断路径提供指导。

{"title":"Metabolomic profiles differentiate between porto-sinusoidal vascular disorder, cirrhosis, and healthy individuals","authors":"Georg Semmler , Oleksandr Petrenko , Juanjo Jose Lozano , Sarah Shalaby , Juan I. Sánchez-Avila , Nara Marella , Thomas Hannich , Katharina Wöran , Lorenz Balcar , Benedikt Simbrunner , Katharina Lampichler , Behrang Mozayani , Michael Trauner , Mattias Mandorfer , Thomas Reiberger , Juan-Carlos García-Pagán , Bernhard Scheiner","doi":"10.1016/j.jhepr.2024.101208","DOIUrl":"10.1016/j.jhepr.2024.101208","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Porto-sinusoidal vascular disorder (PSVD) is a rare and diagnostically challenging vascular liver disease. This study aimed to identify distinct metabolomic signatures in patients with PSVD or cirrhosis to facilitate non-invasive diagnosis and elucidate perturbed metabolic pathways.</div></div><div><h3>Methods</h3><div>Serum samples from 20 healthy volunteers (HVs), 20 patients with histologically confirmed PSVD or 20 patients with cirrhosis were analyzed. Metabolites were measured using liquid chromatography-mass spectrometry. Differential abundance was evaluated with Limma’s moderated t-statistics. Artificial neural network and support vector machine models were developed to classify PSVD against cirrhosis or HV metabolomic profiles. An independent cohort was used for validation.</div></div><div><h3>Results</h3><div>A total of 283 metabolites were included for downstream analysis. Clustering effectively separated PSVD from HV metabolomes, although a subset of patients with PSVD (n = 5, 25%) overlapped with those with cirrhosis. Differential testing revealed significant PSVD-linked metabolic perturbations, including pertubations in taurocholic and adipic acids, distinguishing patients with PSVD from both HVs and those with cirrhosis. Alterations in pyrimidine, glycine, serine, and threonine pathways were exclusively associated with PSVD. Machine learning models utilizing selected metabolic signatures reliably differentiated the PSVD group from HVs or patients with cirrhosis using only 4 to 6 metabolites. Validation in an independent cohort demonstrated the high discriminative ability of taurocholic acid (AUROC 0.899) for patients with PSVD <em>vs.</em> HVs and the taurocholic acid/aspartic acid ratio (AUROC 0.720) for PSVD <em>vs.</em> cirrhosis.</div></div><div><h3>Conclusions</h3><div>High-throughput metabolomics enabled the identification of distinct metabolic profiles that differentiate between PSVD, cirrhosis, and healthy individuals. Unique alterations in the glycine, serine, and threonine pathways suggest their potential involvement in PSVD pathogenesis.</div></div><div><h3>Impact and implications:</h3><div>Porto-sinusoidal vascular disorder (PSVD) is a vascular liver disease that can lead to pre-sinusoidal portal hypertension in the absence of cirrhosis, with poorly understood pathophysiology and no established treatment. Our study demonstrates that analyzing the serum metabolome could reveal distinct metabolic signatures in patients with PSVD, including alterations in the pyrimidine, glycine, serine and threonine pathways, potentially shedding light on the disease's underlying pathways. These findings could enable earlier and non-invasive diagnosis of PSVD, potentially reducing reliance on invasive procedures like liver biopsy and guiding diagnostic pathways.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101208"},"PeriodicalIF":9.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142657121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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