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Can Hepatitis B Virus (HBV) Reactivation Result from a Mild COVID-19 Infection? 轻度新冠肺炎感染是否会导致乙型肝炎病毒（HBV）重新激活？

Livers

Pub Date : 2023-07-25 DOI: 10.3390/livers3030026

I. Braimakis, Sofia Vasileiadi, Eleni-Myrto Trifylli, N. Papadopoulos, M. Deutsch

Hepatitis B virus reactivation (HBVr) is a well-described result of immunosuppressive therapy initiation in various diseases, with the dose and duration of treatment being the main factors determining the probability for reactivation. Such cases have also been described in COVID-19 patients treated with immunosuppressive therapies. Nevertheless, cases of COVID-19 infection that led to HBVr with no concurrent immunosuppressive treatment or any other related cause have also been reported. By that observation, we present a patient followed for a period spanning 20 years with HBeAg negative chronic HBV infection and non-detectable HBV DNA who, after a mild COVID-19 infection treated only with low-dose and short-duration-inhaled corticosteroids (ICS), developed elevated AST and ALT as well as elevated HBV DNA levels. Other etiologies of abnormal liver biochemistries during the diagnostic workout were excluded; thus, the diagnosis of HBV reactivation was established. Treatment with entecavir was initiated, leading to the normalization of AST and ALT levels and a decreasing trend of HBV DNA levels. Since other causes of reactivation were excluded, and the ICS dose and duration were found baring only a very low risk (<1%) for HBVr, COVID-19 infection could be considered the most probable cause of reactivation, hence underlining the need for the close monitoring of those patients.

乙型肝炎病毒再激活（HBVr）是各种疾病中免疫抑制治疗开始的一个众所周知的结果，治疗的剂量和持续时间是决定再激活概率的主要因素。在接受免疫抑制治疗的新冠肺炎患者中也描述了此类病例。尽管如此，也报告了导致HBVr的新冠肺炎感染病例，但没有同时进行免疫抑制治疗或任何其他相关原因。根据这一观察结果，我们介绍了一名患有HBeAg阴性慢性HBV感染和无法检测到HBV DNA的患者，该患者在轻度新冠肺炎感染后仅接受低剂量和短期吸入皮质类固醇（ICS）治疗，出现AST和ALT升高以及HBV DNA水平升高，随访时间长达20年。排除了诊断锻炼期间肝脏生化异常的其他病因；从而确立了HBV再激活的诊断。恩替卡韦开始治疗，导致AST和ALT水平正常化，HBV DNA水平呈下降趋势。由于排除了再激活的其他原因，并且发现ICS剂量和持续时间对HBVr的风险非常低（<1%），因此新冠肺炎感染可被视为再激活的最可能原因，因此强调需要密切监测这些患者。

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引用次数: 0

The Long Game: A Functional Cure Is Possible with Nucleoside Analogues and the Tincture of Time 长期博弈：核苷类似物和时间结构的功能性治疗是可能的

Livers

Pub Date : 2023-07-04 DOI: 10.3390/livers3030024

Nicholas Noverati, V. Yan, Jay W. Jun, D. Halegoua-DeMarzio, H. Hann

Chronic hepatitis B is still prevalent globally. Many patients are treated for many years with nucleos(t)ide analogues to prevent the virus from actively replicating. However, although it typically requires consecutive treatment for more than 10 years, patients can achieve a functional cure from this virus. This case series presents details of functional cures in patients who received varying nucleos(t)ide therapies for an average of 15.3 years before losses of hepatitis B surface antigen and viral load were observed. It is imperative to understand that abbreviating therapy once a functional cure is achieved may be a possibility in treating patients in order to limit the associated costs and side effects of an otherwise lifelong therapy until other cure drugs are approved.

慢性乙型肝炎仍然在全球流行。许多患者使用核苷类似物治疗多年，以防止病毒主动复制。然而，尽管它通常需要连续治疗10年以上，但患者可以从这种病毒中获得功能性治愈。该病例系列介绍了在观察到乙型肝炎表面抗原和病毒载量损失之前，接受不同核苷（t）治疗平均15.3年的患者的功能治疗细节。必须理解，一旦实现功能性治愈，缩短治疗可能是治疗患者的一种可能性，以限制其他终身治疗的相关成本和副作用，直到其他治疗药物获得批准。

引用次数: 0

Special Issue “Liver Fibrosis: Mechanisms, Targets, Assessment and Treatment” 特刊《肝纤维化:机制、靶点、评估与治疗》

Livers

Pub Date : 2023-06-27 DOI: 10.3390/livers3030023

R. Weiskirchen, T. Sauerbruch

Fibrosis is a double-edged sword [...]

纤维化是一把双刃剑[…]

引用次数: 0

Regeneration and Recovery after Acetaminophen Hepatotoxicity. 对乙酰氨基酚肝毒性后的再生与恢复。

Livers

Pub Date : 2023-06-01 DOI: 10.3390/livers3020021

Bharat Bhushan, Udayan Apte

Liver regeneration is a compensatory response to tissue injury and loss. It is known that liver regeneration plays a crucial role in recovery following acetaminophen (APAP)-induced hepatotoxicity, which is the major cause of acute liver failure (ALF) in the US. Regeneration increases proportional to the extent of liver injury upon APAP overdose, ultimately leading to regression of injury and spontaneous recovery in most cases. However, severe APAP overdose results in impaired liver regeneration and unchecked progression of liver injury, leading to failed recovery and mortality. Inter-communication between various cell types in the liver is important for effective regenerative response following APAP hepatotoxicity. Various non-parenchymal cells such macrophages, stellate cells, and endothelial cells produce mediators crucial for proliferation of hepatocytes. Liver regeneration is orchestrated by synchronized actions of several proliferative signaling pathways involving numerous kinases, nuclear receptors, transcription factors, transcriptional co-activators, which are activated by cytokines, growth factors, and endobiotics. Overt activation of anti-proliferative signaling pathways causes cell-cycle arrest and impaired liver regeneration after severe APAP overdose. Stimulating liver regeneration by activating proliferating signaling and suppressing anti-proliferative signaling in liver can prove to be important in developing novel therapeutics for APAP-induced ALF.

肝脏再生是对组织损伤和丧失的一种代偿性反应。众所周知，在美国，对乙酰氨基酚(APAP)引起的肝毒性是导致急性肝衰竭(ALF)的主要原因，肝脏再生在对乙酰氨基酚(APAP)引起的肝毒性恢复中起着至关重要的作用。APAP过量后肝再生与肝损伤程度成正比增加，多数情况下最终导致损伤消退和自发恢复。然而，严重的APAP过量会导致肝再生受损和肝损伤的不受控制的进展，导致恢复失败和死亡。肝内不同类型细胞之间的相互交流对于APAP肝毒性后有效的再生反应是重要的。各种非实质细胞如巨噬细胞、星状细胞和内皮细胞产生对肝细胞增殖至关重要的介质。肝脏再生是由多种增殖信号通路的同步作用精心安排的，这些信号通路涉及多种激酶、核受体、转录因子、转录共激活因子，这些信号通路由细胞因子、生长因子和内源性药物激活。严重APAP过量后，抗增殖信号通路的明显激活会导致细胞周期阻滞和肝脏再生受损。通过激活增殖信号和抑制肝脏中的抗增殖信号来刺激肝脏再生，对于开发apap诱导的ALF的新疗法是重要的。

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引用次数: 0

The role of cytochrome P450 3A4-mediated metabolism in sorafenib and lapatinib hepatotoxicity. 细胞色素P4503A4介导的代谢在索拉非尼和拉帕替尼肝毒性中的作用

Livers

Pub Date : 2023-06-01 Epub Date: 2023-06-19 DOI: 10.3390/livers3020022

Mitchell R McGill, Yihong J Kaufman, Francesca V LoBianco, Mary A Schleiff, Nukhet Aykin-Burns, Grover P Miller

Tyrosine kinase inhibitors (TKIs) are increasingly popular drugs used to treat more than a dozen different diseases, including some forms of cancer. Despite having fewer adverse effects than traditional chemotherapies, they are not without risks. Liver injury is a particular concern. Of the FDA-approved TKIs, approximately 40% cause hepatotoxicity. However, little is known about the underlying pathophysiology. The leading hypothesis is that TKIs are converted by cytochrome P450 3A4 (CYP3A4) to reactive metabolites that damage proteins. Indeed, there is strong evidence for this bioactivation of TKIs in in vitro reactions. However, the actual toxic effects are underexplored. Here, we measured the cytotoxicity of several TKIs in primary mouse hepatocytes, HepaRG cells, and HepG2 cells with and without CYP3A4 modulation. To our surprise, the data indicate that CYP3A4 increases resistance to sorafenib and lapatinib hepatotoxicity. The results have implications for the mechanism of toxicity of these drugs in patients and underline the importance of selecting an appropriate experimental model.

酪氨酸激酶抑制剂（TKIs）是越来越受欢迎的药物，用于治疗十几种不同的疾病，包括某些形式的癌症。尽管与传统化疗相比不良反应较少，但它们并非没有风险。肝损伤是一个特别令人担忧的问题。在美国食品药品监督管理局批准的TKIs中，大约40%会引起肝毒性。然而，人们对其潜在的病理生理学知之甚少。主要假设是TKIs被细胞色素P450 3A4（CYP3A4）转化为损伤蛋白质的反应性代谢产物。事实上，有强有力的证据表明TKIs在体外反应中具有这种生物活性。然而，实际的毒性作用却没有得到充分的研究。在这里，我们测量了几种TKI在具有和不具有CYP3A4调节的原代小鼠肝细胞、HepaRG细胞和HepG2细胞中的细胞毒性。令我们惊讶的是，数据表明CYP3A4增加了对索拉非尼和拉帕替尼肝毒性的耐药性。研究结果对这些药物在患者中的毒性机制具有启示意义，并强调了选择合适的实验模型的重要性。

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引用次数: 0

Mitochondria in Acetaminophen-Induced Liver Injury and Recovery: A Concise Review. 线粒体在对乙酰氨基酚诱导的肝损伤及其恢复中的作用:简要综述。

Livers

Pub Date : 2023-06-01 DOI: 10.3390/livers3020014

Anup Ramachandran, Hartmut Jaeschke

Mitochondria are critical organelles responsible for the maintenance of cellular energy homeostasis. Thus, their dysfunction can have severe consequences in cells responsible for energy-intensive metabolic function, such as hepatocytes. Extensive research over the last decades have identified compromised mitochondrial function as a central feature in the pathophysiology of liver injury induced by an acetaminophen (APAP) overdose, the most common cause of acute liver failure in the United States. While hepatocyte mitochondrial oxidative and nitrosative stress coupled with induction of the mitochondrial permeability transition are well recognized after an APAP overdose, recent studies have revealed additional details about the organelle’s role in APAP pathophysiology. This concise review highlights these new advances, which establish the central role of the mitochondria in APAP pathophysiology, and places them in the context of earlier information in the literature. Adaptive alterations in mitochondrial morphology as well as the role of cellular iron in mitochondrial dysfunction and the organelle’s importance in liver recovery after APAP-induced injury will be discussed.

线粒体是维持细胞能量稳态的关键细胞器。因此，它们的功能障碍会对负责能量密集型代谢功能的细胞(如肝细胞)造成严重后果。在过去的几十年里，广泛的研究已经确定线粒体功能受损是过量对乙酰氨基酚(APAP)引起的肝损伤病理生理学的核心特征，这是美国最常见的急性肝衰竭原因。虽然肝细胞线粒体氧化和亚硝化应激与诱导线粒体通透性转变在APAP过量后得到了很好的认识，但最近的研究揭示了细胞器在APAP病理生理中的作用的更多细节。这篇简明的综述强调了这些新的进展，这些进展确立了线粒体在APAP病理生理中的核心作用，并将它们置于文献中早期信息的背景下。我们将讨论线粒体形态的适应性改变、细胞铁在线粒体功能障碍中的作用以及细胞器在apap诱导损伤后肝脏恢复中的重要性。

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引用次数: 2

Book Review: Weiskirchen, R.; Friedman, S.L. Hepatic Stellate Cells: Methods and Protocols, 1st Ed.; Weiskirchen, R., Friedman, S.L., Eds.; Methods in Molecular Biology 2669; Humana Press: New York, NY, USA, 2023; ISBN 978-1-07-163206-2; eISBN: 978-1-0716-3207-9 书评：Weiskirchen，R。；Friedman，S.L.《肝星状细胞：方法和方案》，第1版。；Weiskirchen，R.，Friedman，S.L.，编辑。；分子生物学方法2669；Humana出版社：美国纽约州纽约市，2023年；ISBN 978-1-07-163206-2；eISBN:978-1-0716-3207-9

Livers

Pub Date : 2023-05-29 DOI: 10.3390/livers3020020

R. Weiskirchen, S. Friedman

Hepatic stellate cells (HSCs) are a liver-specific mesenchymal cell type located in the Dissé space between hepatocytes and sinusoidal endothelial cells [...]

肝星状细胞(HSCs)是一种肝脏特异性间充质细胞类型，位于肝细胞和窦内皮细胞之间的间隙。

引用次数: 0

Expression of Bone Morphogenetic Protein 14 in Liver Disease and Cancer 骨形态发生蛋白14在肝病和癌症中的表达

Livers

Pub Date : 2023-05-25 DOI: 10.3390/livers3020019

J. Sommer, W. Thasler, A. Bosserhoff, C. Hellerbrand

The activation of hepatic stellate cells (HSCs) is the key event of hepatic fibrosis. Furthermore, activated HSCs also play an important role in the progression of hepatocellular cancer (HCC). Bone morphogenetic protein 14 (BMP14) is a member of the TGF-β/BMP superfamily. So far, most studies have analyzed BMP14 in the context of bone and cartilage formation and homeostasis. The aim of this study was to assess the expression and function of BMP14 in liver fibrosis and HCC. The BMP14 expression increased during the in vitro activation of primary human HSCs and also in mouse models of liver fibrosis. In human HCC, as well as non-tumorous liver tissues, there was a significant correlation between the expression of BMP14 and alpha-smooth-muscle actin (α-SMA), an established marker for HSC activation. RNAi-mediated BMP14 suppression in activated HSCs resulted in the reduced expression of the transcription factors inhibitor of differentiation 1 (ID1) and ID2, known targets of BMP signaling. Interestingly, α-SMA and collagen expression was also reduced in BMP14-depleted cells, while treatment with recombinant BMP14 induced ID1, ID2, α-SMA and collagen expression. In human HCC cell lines, treatment with recombinant BMP14 induced proliferation, migratory activity and colony formation. In summary, our data indicate activated HSCs as a major cellular source of enhanced BMP14 expression in fibrotic liver disease and HCC, and show that BMP14 exhibits pro-fibrogenic as well as pro-tumorigenic effects. Future analyses will reveal the potential of this soluble growth factor as a therapeutic target or prognostic marker for the progression of fibrosis and HCC in patients with chronic liver disease.

肝星状细胞(HSCs)的活化是肝纤维化的关键事件。此外，活化的造血干细胞也在肝细胞癌(HCC)的进展中发挥重要作用。骨形态发生蛋白14 (Bone morphogenetic protein 14, BMP14)是TGF-β/BMP超家族成员。到目前为止，大多数研究都是在骨和软骨形成和体内平衡的背景下分析BMP14。本研究的目的是评估BMP14在肝纤维化和HCC中的表达和功能。BMP14的表达在原代人造血干细胞的体外激活过程中增加，在肝纤维化小鼠模型中也增加。在人类HCC以及非肿瘤肝组织中，BMP14的表达与α-平滑肌肌动蛋白(α-SMA)之间存在显著相关性，α-平滑肌肌动蛋白是一种已知的HSC激活标志物。在活化的造血干细胞中，rnai介导的BMP14抑制导致转录因子分化抑制因子1 (ID1)和ID2的表达减少，这是BMP信号传导的已知靶点。有趣的是，在BMP14缺失的细胞中，α-SMA和胶原蛋白的表达也降低，而重组BMP14处理诱导ID1、ID2、α-SMA和胶原蛋白的表达。在人肝癌细胞系中，用重组BMP14处理可诱导增殖、迁移活性和集落形成。总之，我们的数据表明，活化的hsc是纤维化性肝病和HCC中BMP14表达增强的主要细胞来源，并表明BMP14具有促纤维化和促肿瘤作用。未来的分析将揭示这种可溶性生长因子作为慢性肝病患者纤维化和HCC进展的治疗靶点或预后标志物的潜力。

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引用次数: 0

Prevalence and Trends in Hepatitis B & C Virus among Blood Donors in Pakistan: A Regional Transfusion Center Study 巴基斯坦献血者中乙型和丙型肝炎病毒的流行率和趋势：一项区域输血中心的研究

Livers

Pub Date : 2023-05-17 DOI: 10.3390/livers3020018

Tehreem Zorob, Muhammad-Awais Farooqi, A. Ahsan, Abdullah Zaki, M. Rathore, H. Farooqi

Around 118.5 million blood donations are collected annually to save precious lives. The donated blood may also be associated with blood-borne infections. With around 247 million population, Pakistan is an endemic country for viral hepatitis, and there is a high risk of having asymptomatic blood donors among healthy donors. Viral hepatitis is 2.5% prevalent in the general population, and blood donation and its screening have become grave health concerns for Pakistani health authorities. Asymptomatic viral hepatitis needs screening to rule out subliminally diseased individuals, as recommended by the World Health Organization. Knowing the prevalence of the transfusion transmissible infectious (TTIs) agents in healthy blood donors helps assess the disease burden in any population, boosts treatment rates, and precludes dreaded complications in the affected people. The objective of the current study was to determine the prevalence and trends of significant TTIs among blood donors visiting the Armed Forces Institute of Transfusion (AFIT), Rawalpindi, Pakistan. A total of 15,405 blood donors were screened for HBV, HCV, HIV, malaria, and syphilis during this cross-sectional descriptive study. Most donors had an O-positive blood group; AB-negative donors were only 0.7%. Out of the study population, we reported 1.06% HBV, 0.54% HCV, 0.19% HIV, and 0.31% syphilis-positive asymptomatic blood donors. However, no blood donor was found positive for malaria. The Punjab province was reported as the most burdened for TTIs, and youngsters aged 18–27 years were mainly positive, indicating the need to conduct national-level awareness campaigns about TTIs. The stakeholders need to strengthen the blood collection guidelines, and effective performance should be strictly monitored through internal and external audits considering the aim of reaching non-infectious blood products.

每年约有1.185亿人献血，以挽救宝贵的生命。捐献的血液也可能与血源性感染有关。巴基斯坦人口约2.47亿，是病毒性肝炎的流行国家，在健康献血者中出现无症状献血者的风险很高。病毒性肝炎在一般人群中流行率为2.5%，献血及其筛查已成为巴基斯坦卫生当局的严重健康问题。根据世界卫生组织的建议，无症状病毒性肝炎需要筛查以排除潜在患病个体。了解健康献血者中输血传播传染病的流行情况，有助于评估任何人群的疾病负担，提高治疗率，并防止受影响人群出现可怕的并发症。本研究的目的是确定访问巴基斯坦拉瓦尔品第武装部队输血研究所(AFIT)的献血者中显著性tti的患病率和趋势。在这项横断面描述性研究中，共有15405名献血者接受了HBV、HCV、HIV、疟疾和梅毒筛查。大多数献血者是o型阳性血型;ab阴性献血者仅占0.7%。在研究人群中，我们报告了1.06%的HBV, 0.54%的HCV, 0.19%的HIV和0.31%的梅毒阳性无症状献血者。然而，没有发现献血者疟疾呈阳性。据报道，旁遮普省是性传播感染负担最重的省份，18-27岁的年轻人主要持积极态度，这表明有必要开展关于性传播感染的全国性宣传活动。利益攸关方需要加强采血指南，考虑到提供非传染性血液制品的目标，应通过内部和外部审计严格监测采血效果。

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引用次数: 1

Effect of Bergamot Leaves (Citrus bergamia) in the Crosstalk between Adipose Tissue and Liver of Diet-Induced Obese Rats 佛手柑叶对饮食诱导肥胖大鼠脂肪组织与肝脏串扰的影响

Livers

Pub Date : 2023-05-11 DOI: 10.3390/livers3020017

J. S. Siqueira, Erika Tiemi Nakandakare-Maia, T. A. Vieira, T. Palacio, N. A. Grandini, M. Belin, G. A. Nai, F. Moreto, A. Altomare, G. Baron, G. Aldini, F. V. Francisqueti-Ferron, C. Corrêa

The excessive consumption of diets rich in sugar and fat is associated with metabolic manifestations involving adipose tissue and the liver. Bergamot, due to its antioxidant and anti-inflammatory properties, has been used to treat metabolic disorders. This work aimed to verify the effect of Bergamot leaves extract (BLE) on the crosstalk in the adipose tissue–liver axis of obese rats. For 20 weeks, Wistar rats were distributed into two groups: control (Control) and high sugar–fat (HSF) diet groups. Afterwards, the animals were redistributed into three groups for 10 weeks: control diet + vehicle (Control, n = 08), HSF + vehicle (HSF, n = 08), and HSF + BLE (HSF + BLE, n = 08). The BLE was carried out daily by gavage (50 mg/kg). The HSF group presented obesity, hyperglycemia, hypertriglyceridemia, insulin resistance, hepatic microvesicular steatosis, higher inflammation and oxidative stress in the liver and adipose tissue. In comparison to the HSF group, HSF + BLE animals showed protection by reducing the triglyceride levels, insulin resistance, inflammation and oxidative stress in hepatic and adipose tissues. BLE acted on the inflammation and oxidative stress in the adipose tissue–liver axis in obese rats when compared to the HSF group, which may have reflected on the improvement of insulin resistance and dyslipidemia.

过量食用富含糖和脂肪的饮食与脂肪组织和肝脏的代谢表现有关。佛手柑由于其抗氧化和抗炎特性，已被用于治疗代谢紊乱。这项工作旨在验证佛手柑叶提取物（BLE）对肥胖大鼠脂肪组织-肝轴串扰的影响。在20周的时间里，Wistar大鼠被分为两组：对照组（control）和高糖-脂肪（HSF）饮食组。然后，将动物重新分为三组，为期10周：对照饮食+载体（对照，n=08）、HSF+载体（HSF，n=08，和HSF+BLE（HSF+ABL，n=08。BLE每天通过灌胃（50mg/kg）进行。HSF组表现为肥胖、高血糖、高甘油三酯血症、胰岛素抵抗、肝微泡脂肪变性、肝脏和脂肪组织中较高的炎症和氧化应激。与HSF组相比，HSF+BLE动物通过降低肝和脂肪组织中的甘油三酯水平、胰岛素抵抗、炎症和氧化应激表现出保护作用。与HSF组相比，BLE对肥胖大鼠脂肪组织-肝轴的炎症和氧化应激起作用，这可能反映了胰岛素抵抗和血脂异常的改善。

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引用次数: 0

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