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  5. 维生素、矿物质及其他补剂对肝脏功能的影响机制与风险评估

维生素、矿物质及其他补剂对肝脏功能的影响机制与风险评估

深度研究郑建光发表于 2025年10月14日 19:302阅读
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1. 补剂使用现状与肝脏健康的关联背景

在过去的二十年里，全球范围内膳食补剂（Dietary Supplements, DS）的使用呈持续增长态势。尤其在COVID-19大流行期间，公众对免疫系统增强和疾病预防的需求激增，进一步推动了补剂市场的扩大，尽管其功效缺乏足够的科学证据支持 1。膳食补剂涵盖了维生素、矿物质以及其他多种成分，如益生菌、肌酸、氨基酸、草药提取物等。在美国，约50%的普通民众和高达70%的军人定期使用膳食补剂 23。在儿童和青少年群体中，膳食补剂的使用也普遍存在，且非维生素/非矿物质类补剂（如ω-3多不饱和脂肪酸）的使用比例显著增加 4。

肝脏作为人体重要的代谢器官，在膳食补剂的吸收、转化、储存和排泄过程中扮演着核心角色。几乎所有摄入的物质，包括膳食补剂的活性成分及其代谢产物，都需要经过肝脏的处理。因此，肝脏的健康状况直接关系到身体对这些外源性物质的耐受性和处理能力。随着补剂使用率的不断上升，一个核心问题日益凸显：这些广泛使用的维生素、矿物质及其他补剂，在何种情况下会增加肝脏负担，甚至引发肝功能异常？虽然许多补剂在适量摄入时被认为是安全的，甚至有益于健康，但过量使用、不当搭配或在特定个体（如肝病患者）中的使用，可能会对肝脏造成潜在的损伤，引发药物性肝损伤（DILI），其中草药和膳食补剂（HDS）已成为非对乙酰氨基酚DILI的重要诱因 567。因此，深入探讨补剂对肝脏功能的影响机制，评估其潜在风险，对于指导公众合理使用补剂，维护肝脏健康具有重要意义。

2. 肝脏对补剂的代谢与调控机制

肝脏是人体处理各种内源性和外源性物质（包括膳食补剂）的核心器官，其复杂的代谢和调控机制确保了身体的稳态。对补剂而言，肝脏主要通过吸收、转化、储存和排泄等环节发挥作用，其中肝酶系统、胆汁分泌及解毒通路扮演着关键角色。

吸收与首过代谢： 大多数口服的补剂成分，在胃肠道吸收后，会通过门静脉系统首先进入肝脏。这一过程称为“首过代谢”，肝脏在此阶段就开始对补剂进行初步处理。例如，脂溶性维生素（如维生素A、D、E、K）的吸收需要胆汁酸的参与，在小肠内形成胶束后被吸收，随后与乳糜微粒结合进入淋巴系统，最终通过血液循环抵达肝脏。水溶性维生素则主要通过肠道细胞的主动或被动转运吸收，直接进入门静脉系统。

转化与代谢： 肝脏是主要的代谢场所，通过一系列生物转化反应对补剂进行处理。这主要依赖于肝细胞内的多种酶系统。

  • 细胞色素P450（CYP）酶系统： 这是肝脏最重要的药物代谢酶系统之一，对许多补剂（尤其是草药提取物中的植物化学成分）的生物转化至关重要 8。CYP酶家族，特别是CYP3A4、CYP2D6、CYP1A2和CYP2C8等亚型，负责氧化、还原和水解反应，将脂溶性物质转化为更易排泄的水溶性代谢产物 8。例如，一些草药补剂的成分可能诱导或抑制CYP酶的活性，从而影响其他药物或补剂的代谢，甚至产生毒性代谢产物 910。
  • 其他代谢酶： 除了CYP酶，肝脏还含有葡糖醛酸转移酶（UGT）、磺基转移酶等II相酶，通过与补剂成分结合（如葡糖醛酸化、硫酸酯化）进一步提高其水溶性，促进排泄 11。这些酶在解毒过程中发挥关键作用。

储存： 肝脏是多种营养素的重要储存库。例如，脂溶性维生素（尤其是维生素A和D）可以大量储存在肝脏中 12。当膳食摄入不足时，肝脏会释放储存的维生素以维持生理功能；但当摄入过量时，这些脂溶性维生素可能在肝脏中蓄积，导致毒性。例如，维生素A主要储存在肝星状细胞中。矿物质如铁、铜等也以特定形式储存于肝脏。

胆汁分泌与排泄： 胆汁是肝脏产生的一种重要消化液，也参与补剂及其代谢产物的排泄。胆汁酸是胆固醇代谢的终产物，通过胆汁分泌，促进脂质和脂溶性维生素的吸收，并清除肝脏中的脂溶性代谢产物和外源性物质 1314。一些补剂成分或其代谢产物通过胆汁排泄进入肠道，最终随粪便排出体外。胆汁淤积性肝病可能导致脂溶性维生素吸收障碍 121415。

解毒通路： 肝脏具备强大的解毒能力，能够中和有害物质。通过I相（氧化、还原、水解）和II相（结合反应）代谢，肝脏将有毒物质转化为无毒或低毒、易于排泄的形式。这一过程的效率和平衡对肝脏健康至关重要。补剂的过量摄入或某些成分的潜在毒性，可能超出肝脏的解毒能力，导致活性氧自由基生成增加、线粒体功能障碍或直接细胞损伤，从而引发肝功能异常。例如，抗氧化剂硒（以硒蛋氨酸形式补充）已被证明可以减轻氟化物诱导的肝细胞凋亡和炎症反应 16。然而，肝脏对毒素的过度负担，可能导致氧化应激和炎症反应，进而引发肝损伤。

3. 不同类型补剂对肝脏的潜在影响分析

3.1 维生素类补剂

维生素是维持生命活动和身体健康不可或缺的微量有机物。根据其溶解性，维生素可分为脂溶性维生素（A、D、E、K）和水溶性维生素（B族、C）。尽管适量补充维生素对健康有益，但过量摄入，特别是脂溶性维生素，由于其在体内易于蓄积的特性，可能对肝脏造成潜在负担，甚至引发肝损伤。水溶性维生素通常更容易随尿液排出，但高剂量下仍可能对肝脏代谢带来挑战。

3.1.1 脂溶性维生素（A、D、E、K）

脂溶性维生素的特点是可在脂肪组织和肝脏中储存，因此过量摄入易导致蓄积中毒。

  • 维生素A： 维生素A主要以视黄醇酯的形式储存在肝脏的肝星状细胞（Hepatic Stellate Cells, HSCs）中。正常情况下，HSCs储存的维生素A有助于维持肝脏稳态。然而，长期或急性过量摄入维生素A（通常超过推荐剂量的10倍以上），会导致HSCs过度活化并储存大量维生素A。临床案例显示，过量维生素A中毒可表现为非特异性症状，如皮肤干燥、脱发、食欲不振等，严重时可导致肝功能异常，包括血清转氨酶（ALT、AST）升高、碱性磷酸酶（ALP）升高，甚至肝脾肿大、门静脉高压和肝硬化 17。例如，有报告指出，一名患有21-三体综合征的儿童在接受维生素A衍生物阿维A治疗皮肤病后，出现了肝酶升高，最终因肝毒性而停止治疗 17。这表明在特定情况下，即使是治疗性剂量，也可能对肝脏造成负担。成人长期摄入每日超过30,000 IU维生素A可能导致慢性肝毒性。

  • 维生素D： 维生素D在肝脏中首先被25-羟化酶转化为25-羟基维生素D [25(OH)D]，这是其在血循环中的主要形式，随后在肾脏中进一步活化为1,25-二羟基维生素D [1,25(OH)D]，发挥其生物学功能。虽然维生素D中毒相对罕见，但超高剂量补充仍可能引起肝脏问题。过量的维生素D会导致高钙血症，从而可能诱发肝脏钙化或损害肝功能。有研究表明，维生素D及其受体（VDR）在肝纤维化和非酒精性脂肪肝（NAFLD）的病理生理过程中发挥作用。例如，VDR可以抑制YAP（Yes-associated protein）的转录活性，从而减轻四氯化碳（CCl₄）诱导的肝纤维化 18。此外，补充1,25-二羟基维生素D [1,25(OH)D]已被证明可通过抑制M1巨噬细胞极化，改善NAFLD中的肝脏脂肪变性并减少脂质蓄积 19。然而，这些是维生素D的潜在治疗益处，并不意味着无限量补充是安全的。对于严重胆汁淤积的患者，脂溶性维生素吸收不良，可能需要补充水溶性维生素制剂，以防止缺乏症 202122。

  • 维生素E： 维生素E是一种重要的脂溶性抗氧化剂，能保护细胞膜免受氧化损伤。在NAFLD等肝脏疾病中，维生素E被认为具有一定的保护作用。然而，极高剂量的维生素E补充（例如每日超过800 IU）可能增加出血风险，并有报道称在少数情况下与肝功能异常相关。但总体而言，相对于维生素A和D，维生素E引起肝损伤的风险较低。一项针对晚期肝硬化患者的研究显示，口服水溶性维生素E（tocofersolan）700毫克/天，持续4周，耐受性良好，未观察到显著肝毒性，并能改善血浆维生素E水平和贫血，但对红细胞膜脂质组成无显著影响 22。

  • 维生素K： 维生素K主要参与凝血因子的合成。正常情况下，维生素K对肝脏的毒性非常低。即使是高剂量补充，也很少报告引起肝损伤。然而，对于新生儿，有研究曾关联肌内注射维生素K增加儿童癌症风险，但这与肝损伤无直接关系，且目前已不推荐这种用法 20。

3.1.2 水溶性维生素（B族、C）

水溶性维生素通常不易在体内蓄积，过量部分会随尿液排出，因此其引起肝脏毒性的风险远低于脂溶性维生素。然而，在极高剂量下，或在特定个体中，仍可能对肝脏代谢带来负担。

  • 维生素B族： B族维生素包含多种成员，如B1（硫胺素）、B2（核黄素）、B3（烟酸）、B5（泛酸）、B6（吡哆醇）、B7（生物素）、B9（叶酸）和B12（钴胺素）。它们在肝脏代谢中扮演辅酶角色，参与能量代谢、氨基酸代谢和DNA合成等过程。

    • 维生素B6（吡哆醇）： 虽然维生素B6在一般推荐剂量下是安全的，但长期超高剂量（如每日数百毫克）可能导致神经毒性，表现为感觉神经病变。至于其与肝酶升高的直接关联，目前的证据相对有限。然而，一项针对稀有皂苷（一种补充剂）的90天毒性研究发现，高剂量稀有皂苷可导致大鼠肝脏炎症变化，并使丙氨酸转氨酶（ALT）、乳酸脱氢酶（LDH）和碱性磷酸酶（AKP）水平显著升高，同时改变了维生素B6的代谢途径，提示肝脏损伤与B6代谢的改变可能存在关联 23。这间接提示了在某些复杂的补充剂相互作用中，维生素B6代谢可能受影响。
    • 烟酸（维生素B3）： 大剂量烟酸（尤其是在降血脂治疗中）是已知可引起肝毒性的水溶性维生素。其可导致转氨酶升高，甚至引发药物性肝炎。通常，这种肝毒性与剂量相关，且可逆。

  • 维生素C（抗坏血酸）： 维生素C也是一种强大的水溶性抗氧化剂。在适量范围内，它有助于保护肝脏免受氧化应激损伤 24。例如，在对乙酰氨基酚（APAP）诱导的小鼠肝损伤模型中，维生素C显示出显著的肝保护作用，能有效降低血清肝酶水平并减轻氧化应激 24。然而，超高剂量的维生素C理论上可能增加草酸肾结石的风险，但在肝脏毒性方面，直接证据较少。一般认为，健康个体即使摄入数克维生素C，肝脏也能有效处理，很少引起临床意义上的肝功能异常。然而，在某些特殊情况下，如铁过载的患者，超高剂量的维生素C可能通过促进铁的吸收，加剧肝脏的氧化应激损伤 25。

总体而言，水溶性维生素在通常剂量下对肝脏是安全的，但在极端高剂量或特定病理生理条件下，仍需警惕其潜在影响。

3.2 矿物质类补剂

矿物质是构成人体组织、维持生理功能和生化代谢所必需的微量营养素。根据其在人体内的含量和日需求量，可分为必需矿物质（如硒、锌、铁、铜等）和非必需矿物质（如铅、镉、砷等，通常指具有毒性且非人体必需的元素）。肝脏是矿物质代谢和储存的重要器官，因此矿物质的摄入量（无论是缺乏还是过量）都可能对肝脏功能产生显著影响。

3.2.1 必需矿物质（硒、锌、铁）

必需矿物质在生理浓度下对维持肝脏健康至关重要，但过量摄入同样可能带来毒性。

  • 硒： 硒是一种重要的微量元素，通过硒蛋白（如谷胱甘肽过氧化物酶，GPx）参与抗氧化防御，保护肝细胞免受氧化损伤 26。适量的硒对维持肝功能和预防肝病具有保护作用。例如，硒已被证实可以缓解镉引起的肝损伤和铁死亡，其机制可能与调节SLC7A11/GPX4信号通路和脂质过氧化有关 27。纳米硒（Nano-Selenium, NSe）也可以通过降低氧化应激和激活Nrf2通路来减轻镉引起的急性肝毒性 28。此外，富硒长双歧杆菌（SeBL）能有效抑制酒精和高脂饮食诱导的肝脏氧化应激、脂肪生成和炎症，从而保护肝脏 29。在动物实验中，硒缺乏会导致肝脏硒含量显著减少，并伴随肝硬化和肝脏重量的增加，提示硒在维持肝脏结构和功能完整性方面的重要性 30。然而，过量摄入硒（通常认为每日超过400微克）可能导致硒中毒，表现为脱发、指甲变脆、胃肠道症状等。

  • 铁： 铁是血红蛋白的重要组成部分，参与氧气运输和细胞呼吸。肝脏是铁的主要储存器官。然而，铁过载对肝脏具有显著的毒性。当体内铁含量过高时，过量的铁会在肝细胞中积累，导致脂质过氧化、蛋白质氧化和DNA损伤，引发肝细胞坏死和纤维化。这种损伤机制被称为“铁死亡”（ferroptosis），矿物质失衡在其中扮演重要角色，如NAFLD中就涉及铁代谢紊乱与氧化应激、线粒体功能障碍等的关联 31。

    • 铁过载的临床表现： 遗传性血色病（Hereditary Hemochromatosis, HH）是一种常见的铁代谢紊乱疾病，由于HFE基因突变导致铁吸收增加，引起肝脏、心脏、胰腺等多个器官铁沉积，最终可能发展为肝硬化和肝癌 32。非输血依赖型地中海贫血患者也常伴有肝脏铁过载，且与年龄、血红蛋白水平和累计输血量等临床风险因素相关 33。在儿童血液恶性肿瘤患者中，超过一半的患者存在肝脏铁过载，且血清铁蛋白水平（>1000 ng/ml）与肝脏铁浓度（LIC）显著相关 34。
    • 巨噬细胞与铁死亡： 巨噬细胞在肝脏铁稳态和肝缺血/再灌注（I/R）损伤中发挥重要作用。在铁过载条件下，肝脏I/R损伤会导致肝细胞铁死亡和巨噬细胞胞外陷阱（METs）增加，进一步加剧肝细胞损伤 35。
    • 与铜的相互作用： 有趣的是，口服铁补充剂可以在一定程度上缓解铜中毒引起的铁吸收和利用改变，提示铁和铜在肝脏代谢中存在复杂的相互作用 36。

3.2.2 非必需矿物质（铜、铅）

一些在生理功能中不被认为必需或仅在极低浓度下发挥作用的矿物质，如铅、镉、汞等，通常具有较强的毒性。即使是必需矿物质，在超生理剂量下也会表现出毒性，例如铜。

  • 铜： 铜是多种酶（如细胞色素c氧化酶、超氧化物歧化酶）的组成部分，在能量代谢、铁代谢和抗氧化防御中发挥关键作用。肝脏是铜代谢和排泄的核心器官。然而，铜在自由离子状态下，可以参与类芬顿反应（Fenton-like reactions）产生破坏性的活性氧自由基。
    • 铜中毒与肝损伤： 过量摄入铜，特别是通过一些不规范的膳食补剂（如健身补剂），可能导致严重的铜中毒，进而引发肝损伤。有案例报道，一名32岁的健身爱好者因使用多种营养和增强体能补剂，导致严重的铜中毒，出现脑病、爆发性肝衰竭和横纹肌溶解症，其症状甚至类似于威尔逊病 37。这表明非法添加或超标的矿物质成分（如铜）可能导致肝细胞坏死和胆汁淤积。
    • 铜在NAFLD中的作用： 在非酒精性脂肪肝（NAFLD）的病理生理学中，铜的失衡也扮演着重要角色，可能通过影响氧化应激、线粒体功能障碍和炎症反应来促进疾病进展 31。
    • 镉与铜： 膳食铜的补充可以影响多氯联苯（PCB126）在啮齿动物肝脏中的毒性，并改变肝脏的金属稳态，导致肝脏铜水平加倍，同时减少硒、锰、锌和铁等其他必需金属的含量 38。这表明不同金属元素之间存在复杂的相互作用，可能共同影响肝脏的解毒和损伤过程。
    • 镉： 镉是一种环境污染物，长期暴露可导致肝脏损伤。谷物麸皮补充剂在低浓度镉暴露下可能减少肾脏镉积累，但在高浓度暴露下对镉毒性预防效果不明显 39。硒（尤其是纳米硒或硒代胱氨酸）已被证实可有效拮抗镉诱导的肝损伤，其机制涉及减轻氧化应激、抑制过度自噬激活和恢复线粒体自噬流 272840。这再次强调了矿物质间相互作用的重要性。
    • 治疗潜力： 膳食姜黄素补充剂可以通过调节PXR/NF-κB信号通路来缓解铜诱导的肝损伤，显示出其作为铜中毒治疗靶点的潜力 41。

总体而言，矿物质补剂对肝脏的影响是双刃剑。必需矿物质在适量时是维持生命不可或缺的，但无论是过量还是缺乏，都可能对肝脏造成损害。非必需矿物质或在膳食补剂中非法添加的矿物质，则可能直接引发严重的肝毒性。因此，在使用矿物质补剂时，需严格控制剂量，并警惕其潜在的相互作用和毒性风险。

3.3 其他常见补剂

除了维生素和矿物质，市场上还充斥着各种各样的“其他”补剂，它们在健身、肠道健康、体重管理等领域广受欢迎。然而，这些补剂的成分复杂性及其对肝脏的潜在影响往往被忽视。

  • 肌酸： 肌酸是一种天然存在于肌肉中的化合物，在能量代谢中扮演关键角色，被广泛用作提高运动表现的膳食补剂。肌酸补充剂在健康人群中通常被认为是安全的。多项研究表明，短期（如5天）或长期（如5年）补充肌酸，对健康个体的肝酶（如ALT、AST）通常没有显著影响，不会增加肝脏负担 。然而，肌酸的代谢产物肌酐主要通过肾脏排泄，对肾功能不全者可能构成风险。尽管如此，肌酸本身在肝脏的尿素循环中会转化为肌酐，对于已存在肝功能障碍或肝病患者，理论上可能增加肝脏的代谢负荷，尤其是在高剂量摄入时。因此，对于肝病患者，补充肌酸的风险需谨慎评估。

  • 益生菌与益生元： 益生菌是活的微生物，益生元是选择性发酵的成分，能促进特定肠道微生物的生长。它们通过“肠-肝轴”在肝脏健康中发挥着越来越被认可的作用 424344。

    • 保护作用： 肠道菌群失调（肠道菌群失衡）是多种肝脏疾病（如非酒精性脂肪肝病, NAFLD）发生发展的重要因素之一 424344。乳酸杆菌等益生菌能够调节肠道菌群构成，减少肠道通透性，从而降低内毒素（如脂多糖LPS）从肠道进入肝脏的量，减轻肝脏炎症反应和氧化应激 424445。例如，有研究表明，Akkermansia muciniphila（一种益生菌）能够通过调节肠道菌群组成和代谢，减轻对乙酰氨基酚（APAP）诱导的肝损伤，降低血清ALT和AST水平，并缓解氧化应激和炎症反应 46。益生菌和益生元的补充被认为是恢复肠道菌群平衡、改善NAFLD的潜在治疗策略 4244。肠道菌群还能影响胆汁酸代谢，而胆汁酸失调与能量消耗减少、脂肪生成增加和炎症加剧有关 42。
    • 过度补充的风险： 尽管益生菌通常被认为是安全的，但在某些极端情况下，如免疫功能严重受损的患者或存在肠道屏障功能障碍（“肠漏”）的情况下，过度补充或不当使用益生菌可能导致菌血症或真菌血症。此外，肠道菌群的显著失衡，即使是由所谓的“有益”菌过度繁殖引起，也可能影响肝脏的代谢稳态。然而，直接证据表明益生菌或益生元引起健康个体肝损伤的案例非常罕见。

  • 草药及复合补充剂： 草药和复合补充剂是DILI（药物性肝损伤）的重要原因，且其发生率在全球范围内呈上升趋势 4748。在一些国家和地区，草药补剂甚至成为非对乙酰氨基酚DILI的主要诱因。

    • 绿茶提取物（Green Tea Extract, GTE）： 绿茶及其提取物因其富含儿茶素（特别是EGCG）而被广泛宣传具有抗氧化、抗癌等多种健康益处。然而，高剂量的绿茶提取物已被证实具有肝毒性。动物实验表明，高浓度绿茶提取物可引起大鼠肝细胞的急性毒性，导致线粒体功能障碍和细胞坏死，其中EGCG被认为是主要的致毒成分 4950。剂量依赖性研究指出，低中剂量的绿茶多酚具有肝保护作用，而高剂量则可能通过促氧化作用引起肝毒性 51。
    • 何首乌（Polygonum multiflorum Thunb.）： 何首乌是一种常用中药，但在临床应用中，其引起的肝损伤报告日益增多，已引起广泛关注 5253545556。何首乌导致的肝损伤通常具有特异性，其毒性成分和具体机制仍在深入研究中。研究表明，何首乌的蒽醌类和二苯乙烯苷类化合物可能是主要的肝毒性物质 535556。何首乌引起的肝损伤机制可能涉及氧化磷酸化、胆汁酸排泄、代谢途径改变、遗传因素以及免疫调节异常等 5556。中国DILI数据显示，草药补剂是导致DILI的重要诱因，其中何首乌及其制剂占有相当高的比例 5455。一项研究通过机器学习方法预测并体外验证，发现何首乌中的二蒽酮和蒽醌类化合物具有较高的DILI风险 53。
    • 其他草药和复合补剂： 其他草药如麻黄、卡瓦胡椒、黑升麻等，以及许多成分复杂的复合减肥、增肌补剂，也曾有导致肝损伤的报道。这些产品往往含有多种成分，成分间的相互作用、非法添加、生产过程中的污染或标准不一，都可能增加其对肝脏的潜在风险。一些草药成分可能通过免疫介导机制（如诱发自身免疫反应，或与特定HLA基因型相关）或直接细胞毒性机制引发肝损伤 47。例如，药物性肝损伤（DILI）的发生机制复杂，可能涉及活性代谢产物的形成，诱导线粒体氧化应激和线粒体通透性转换孔开放，最终导致细胞炎症、凋亡和坏死 57。
    • 风险评估挑战： 草药和复合补剂的成分复杂性使得其肝毒性评估更具挑战性。许多消费者对这些产品的风险认知不足，盲目追求“天然无害”，这增加了肝损伤的发生率。因此，对这些补剂的成分进行严格的质量控制和安全性评估至关重要。

3.3.1 肌酸

肌酸作为一种提高运动表现和肌肉力量的常见补剂，其对肝脏的影响是人们关注的焦点之一。研究表明，在接受化疗药物阿霉素治疗的大鼠模型中，补充肌酸能减轻阿霉素诱导的肝损伤，包括肝纤维化、炎症、氧化应激和细胞衰老，提示肌酸可能对肝脏具有保护作用 58。肌酸主要在肝脏和肾脏合成，并在体内转化为肌酐，通过肾脏排泄。这意味着肝脏参与了肌酸的合成和部分代谢，但其主要排泄途径是肾脏。因此，对于肾功能不全的个体，肌酸补充可能带来额外的风险。

尽管如此，肌酸在肝脏的尿素循环中扮演角色，对于已存在肝功能障碍或肝病（如非酒精性脂肪肝、肝硬化）的患者，高剂量的肌酸补充理论上可能增加肝脏的代谢负担。由于肝病患者的肝脏解毒和代谢能力下降，即使是正常剂量的补剂也可能超出其处理能力，从而潜在地加剧肝损伤。然而，目前缺乏足够针对肝病患者补充肌酸的安全性研究。因此，对于这类特殊人群，在补充肌酸前应咨询医生，并密切监测肝功能指标。

3.3.2 益生菌与益生元

益生菌（Probiotics）是活的微生物，益生元（Prebiotics）是选择性发酵的成分，它们被广泛应用于改善肠道健康。近年来，肠道菌群与肝脏健康之间的“肠-肝轴”概念日益受到关注。益生菌和益生元通过调节肠道菌群，影响肠道屏障功能，减少肠源性毒素（如内毒素LPS）进入肝脏，从而可能对肝脏产生有益影响。

  • 保护作用： 研究表明，乳酸杆菌等益生菌能有效调节肠道菌群，改善肠道通透性，减轻肝脏的炎症反应和氧化应激，这对于非酒精性脂肪肝病（NAFLD）等肝脏疾病具有潜在的治疗价值 5960。例如，姜黄素补充剂通过调节肠道菌群依赖的胆汁酸代谢，显著降低了非酒精性单纯性脂肪肝（NASFL）患者的肝脏脂肪含量 59。同样，水飞蓟素（Silymarin）补充剂可能通过调节肠道微生物群来改善代谢功能障碍相关脂肪性肝病（MASLD）患者的肝脏硬度 61。这些研究强调了益生菌或肠道菌群调节剂在改善肝脏健康方面的潜力。

  • 潜在风险： 尽管益生菌通常被认为是安全的，但在特定人群中仍需警惕潜在风险。例如，在免疫功能严重受损、重症监护患者或存在肠道屏障功能严重受损（“肠漏”）的个体中，活的益生菌可能穿透肠道屏障，进入血液循环，导致菌血症或真菌血症，从而引发全身性感染，间接对肝脏造成损害。此外，过度或不当补充益生菌，即使不会直接造成肝损伤，也可能导致肠道菌群过度失衡，例如小肠细菌过度生长（SIBO），从而影响营养吸收和代谢，间接影响肝脏健康。然而，在健康个体中，益生菌或益生元引起肝脏损伤的直接案例非常罕见。

3.3.3 草药及复合补充剂

草药和复合补充剂是导致药物性肝损伤（DILI）的重要且日益增长的原因。这类产品通常含有多种活性成分，其成分的复杂性、剂量的不确定性以及可能的非法添加物，使得其对肝脏的风险评估更具挑战性。一项对Wistar大鼠的安全性评估显示，一种由多种药用植物配制的复合草药补剂Bon-santé cleanser®在1000 mg/kg剂量下引起了肝脏和心脏的轻度炎症，提示其潜在的肝损伤风险 62。

  • 绿茶提取物（Green Tea Extract, GTE）： GTE因富含儿茶素（特别是表没食子儿茶素没食子酸酯, EGCG）而被广泛宣传具有抗氧化和健康益处。然而，高剂量的GTE已明确与肝损伤风险相关。动物实验显示，高浓度GTE可引起大鼠肝细胞的急性毒性，导致线粒体功能障碍和细胞坏死。这种肝毒性具有剂量依赖性，低中剂量的绿茶多酚可能具有肝保护作用，而高剂量则可能通过促氧化作用引发肝毒性。

  • 何首乌（Polygonum multiflorum Thunb.）： 何首乌是一种常见中药，但在临床应用中，其引起的肝损伤报告日益增多，已引起广泛关注。何首乌导致的肝损伤通常具有特异性，其毒性成分被认为是蒽醌类和二苯乙烯苷类化合物。何首乌引起的肝损伤机制复杂，可能涉及氧化磷酸化、胆汁酸排泄异常、代谢途径改变、遗传易感性以及免疫调节异常等。由于其高发的肝毒性风险，许多国家已对其使用提出严格警示或限制。

  • 其他草药和复合补剂： 除了绿茶提取物和何首乌，多种草药和复合补充剂也曾被报道引起肝损伤，例如麻黄、卡瓦胡椒（kava）、黑升麻等。许多市售的减肥、增肌或“排毒”类复合补剂，由于成分复杂，常含有未申报的药物成分、重金属或其他有毒物质，或成分之间存在协同毒性，进一步增加了肝损伤的风险。其损伤机制可能包括：

    • 直接细胞毒性： 某些草药成分或其代谢产物可直接损伤肝细胞。
    • 免疫介导损伤： 部分草药可能诱发自身免疫反应，或在特定遗传背景（如HLA基因型）个体中引起免疫介导的肝损伤。
    • 药物相互作用： 草药成分可能影响肝脏的药物代谢酶（如CYP450系统），从而改变其他药物的代谢，增加毒性或降低药效。
    • 污染与掺假： 产品生产过程中的污染（如重金属、农药、真菌毒素）或非法添加处方药成分（如类固醇、西布曲明等），是导致肝损伤的重要原因。

总体而言，草药和复合补充剂的风险评估更为复杂，消费者应特别警惕来路不明、声称“快速见效”或“神奇功效”的产品。在服用任何草药或复合补剂之前，务必咨询医生或药师，特别是对于本身有肝脏疾病或正在服用其他药物的人群。

4. 补剂致肝损伤的关键影响因素

补剂对肝脏的潜在影响并非一概而论，而是受到多种因素的复杂调控。除了补剂本身的化学性质和剂量外，个体的生理状态、使用方式、其他药物或补剂的并用等都可能显著影响其肝毒性风险。

4.1 剂量与使用时长

剂量和使用时长是决定补剂是否引起肝损伤的最直接且重要的因素。任何物质，即使是维持生命必需的营养素，在超过生理需求的高剂量下都可能产生毒性。区分“生理需求剂量”与“药理剂量”是理解这一概念的关键。

  • 生理需求剂量： 指维持正常生理功能所需的最低有效剂量。在这个剂量范围内，补剂通常被肝脏有效代谢，并不会对肝脏造成负担，甚至可能发挥保护作用。例如，适量的维生素和矿物质是肝脏正常运作所必需的。

  • 药理剂量： 指远高于生理需求剂量，旨在产生特定治疗或药理作用的剂量。在此剂量下，补剂可能会超出肝脏的正常代谢和解毒能力，从而增加肝脏负担，甚至引发损伤。例如，大剂量烟酸（维生素B3）用于降血脂时，已知可引起转氨酶升高和药物性肝炎。

短期冲击剂量与长期超量：

  • 短期冲击剂量： 某些补剂，如维生素D，有时会采用短期高剂量冲击疗法来迅速纠正严重缺乏。例如，单次或短期内高剂量补充维生素D（如数万甚至数十万IU），旨在迅速提升血浆25(OH)D水平。虽然这种方法在临床指导下通常是安全的，但如果频繁或无指征地进行超大剂量补充，可能导致维生素D在体内迅速蓄积，引起高钙血症，进而间接对肝脏造成压力，或在极端情况下加重肝脏钙化风险。虽然维生素D本身具有抗纤维化、抗炎和胰岛素敏感特性，但其代谢产物对肝脏的影响仍需关注 63。

  • 长期超量： 相较于短期冲击剂量，长期持续性地超量摄入补剂对肝脏的代谢储备消耗更大，风险也更高。例如，年长者长期服用复合维生素，如果其中某些脂溶性维生素（如维生素A）的含量远超推荐量，长期累积可能导致肝脏蓄积性损伤。肝脏会不断动员其解毒酶系统来处理这些过量的外源性物质，长期处于高负荷工作状态可能导致肝细胞损伤、氧化应激增加，甚至诱发炎症和纤维化。铁剂的长期超量补充，尤其是在非缺铁性贫血患者中，可导致铁在肝脏中过度沉积，引发铁过载性肝病。此外，一些草药补剂的长期超量使用，即使是所谓的“天然”成分，也可能因其活性成分的慢性刺激或蓄积性毒性而导致肝脏慢性损伤。动物实验中，对杀虫剂氯氰菊酯和β-氟氯氰菊酯的亚急性毒性研究显示，即使是较低剂量（0.1 LD50）长期暴露（28天）也会引起大鼠肝脏的生化和组织学改变，包括转氨酶升高、肝糖原和蛋白降低以及肝细胞空泡化、坏死等，且β-氟氯氰菊酯的肝毒性更大 64。这表明，长期暴露于低剂量有害物质同样可能对肝脏造成损害。

4.2 个体易感性

除了剂量和使用时长，个体自身的生理状态和遗传背景在补剂致肝损伤中扮演着关键角色。不同个体对补剂的反应存在显著差异，这种差异被称为个体易感性。某些特定因素可放大补剂对肝脏的毒性作用，使肝脏更易受到损害。

  • 基础肝病（如非酒精性脂肪肝病NAFLD、肝硬化）： 患有基础肝病的个体，其肝脏功能往往已经受损，肝细胞储备和解毒能力下降，对药物或补剂的耐受性远低于健康人群。

    • NAFLD患者： NAFLD患者的肝脏已存在脂肪堆积、炎症和纤维化，其肝脏代谢酶活性可能异常，线粒体功能受损，更容易发生氧化应激。在这种情况下，即使是健康人能耐受的补剂剂量，也可能对NAFLD患者的肝脏造成额外的负担，加速疾病进展。例如，铁过载已被证实会加重NAFLD的病理生理过程，而NAFLD患者若不慎补充过量铁剂，将面临更高的肝损伤风险。
    • 肝硬化患者： 肝硬化患者的肝脏结构和功能严重破坏，肝细胞数量显著减少，血流动力学改变，代谢和排泄能力极低。对于这类患者，任何可能增加肝脏负担的外源性物质都应严格限制。例如，肝硬化患者补充草药制剂的风险极高，因为许多草药成分的代谢需要肝脏的高度参与，并且可能存在未知的肝毒性。一项关于酒精性肝病的研究发现，肠道菌群失调在酒精性肝损伤中起关键作用，而肝硬化患者常伴有严重的肠道菌群失调和肠道屏障功能障碍，这可能使其对益生菌或益生元的反应也不同于健康个体 6566。

  • 遗传因素（如药物代谢酶基因多态性）： 人体对药物和补剂的代谢能力受到遗传因素的影响。药物代谢酶，特别是细胞色素P450（CYP）酶系统的基因多态性，可以导致个体间酶活性的巨大差异。

    • CYP酶多态性： 某些个体可能因为CYP酶基因突变而成为“慢代谢者”或“快代谢者”。慢代谢者对某些补剂的清除速度较慢，导致药物或其有毒代谢产物在体内蓄积，从而增加肝毒性风险。例如，部分草药成分的代谢途径可能受特定CYP酶亚型的影响，遗传多态性可能导致其代谢异常，从而引发肝损伤。
    • HLA基因型： 遗传因素还可能影响免疫介导的肝损伤。例如，研究发现特定的HLA（人类白细胞抗原）基因型与某些药物或草药引起的肝损伤风险增高相关，这提示了个体免疫反应在补剂相关DILI中的作用。例如，对于一些草药提取物，携带特定HLA基因型的个体可能更容易发生免疫介导的肝损伤。

  • 肠道屏障功能（如肠漏综合征）： 肠道屏障是抵御肠道内有害物质进入体内的第一道防线。肠道屏障功能受损（即“肠漏症”）意味着肠壁通透性增加，允许细菌产物（如脂多糖LPS）、毒素和未完全消化的食物成分进入血液循环，并通过门静脉系统到达肝脏，从而加重肝脏负担并引发炎症 67686970。

    • 肠漏与肝损伤： 慢性肝病，包括NAFLD和酒精性肝病，常常伴有肠道屏障功能障碍和肠道菌群失调 66。在这种情况下，即使是少量摄入的补剂，如果其成分能够影响肠道菌群或进一步损害肠道屏障，也可能通过“肠-肝轴”间接对肝脏造成损害。例如，益生元（如低聚果糖）在一定程度上可以改善肠道菌群，从而减轻环境毒素砷诱导的肝损伤 71。反之，如果补剂导致肠道菌群进一步失衡或加剧肠漏，则可能恶化肝脏状况。

案例说明：肝病患者补充铁剂或草药的高风险

  • 铁剂补充： 对于非缺铁性贫血的肝病患者，特别是伴有肝脏铁超载的患者（如慢性丙型肝炎、NAFLD患者），额外补充铁剂会显著增加肝脏损伤的风险。过量的铁会在肝脏中蓄积，导致氧化应激和肝细胞损伤，加速肝纤维化和肝硬化进程。对于这类患者，应定期监测血清铁蛋白和肝脏铁含量，并在医生指导下进行补铁治疗。
  • 草药补剂： 草药补剂诱导的肝损伤（HILI）在全球范围内呈上升趋势，并且在一些地区已成为DILI的主要诱因 7273。对于肝病患者，服用草药补剂的风险尤为突出。例如，在亚洲国家，传统草药何首乌是导致DILI的常见原因之一，其肝毒性机制复杂，个体差异大。肝病患者由于肝脏代谢能力受损，更难以处理草药中的潜在肝毒性成分，从而更容易发生严重肝损伤，甚至导致急性肝衰竭 74。即使是一些看似“天然无害”的复合草药补剂，也可能因成分复杂、相互作用或掺假而对肝脏造成损害 72。

综上所述，个体易感性是评估补剂肝毒性风险时不可忽视的重要因素。在考虑使用任何补剂前，尤其是对于存在基础肝病、已知遗传多态性或肠道功能异常的个体，务必进行全面的医学评估，并在专业人士指导下谨慎选择和使用。

4.3 补剂成分复杂性

补剂，尤其是复合型补剂，往往包含多种维生素、矿物质、草药提取物及其他生物活性成分。这种成分的复杂性使得其对肝脏的影响远非单一成分作用的简单叠加，而是涉及复杂的相互作用，可能导致协同毒性、拮抗作用或代谢通路干扰，进而对肝脏代谢网络产生深远影响。

4.3.1 维生素-矿物质相互作用

维生素和矿物质在体内的吸收、代谢和功能发挥上存在紧密的相互作用，这些相互作用可能影响其在肝脏中的处理过程，甚至改变其毒性潜力。

  • 维生素A过量抑制维生素D吸收： 维生素A和维生素D在体内共享某些吸收和代谢通路，并可能在功能上存在拮抗作用。例如，有研究表明，高剂量的维生素A可能会干扰维生素D的吸收和利用，从而间接影响其在肝脏中的活化和储存，甚至可能影响肝脏对维生素D的毒性阈值。在某些情况下，过量的维生素A还可能增强维生素D的潜在毒性，尽管具体机制尚不完全清楚。

  • 铁与维生素、其他矿物质的相互作用： 铁的代谢受到多种营养素的影响。维生素C能显著促进非血红素铁的吸收，对于铁缺乏症患者是有益的。然而，一些植物化学物质（如茶多酚、草酸）可以螯合铁，抑制其吸收。

    • 铁过载与维生素E、硒： 铁过载可导致严重的氧化应激，而维生素E和硒作为重要的抗氧化剂，可以协同作用减轻铁诱导的氧化损伤。例如，硒与高剂量维生素E联合使用，能有效保护顺铂诱导的大鼠肾脏、肝脏和晶状体组织的氧化损伤 75。这提示了在特定病理条件下，不同补剂成分的协同抗氧化作用可能对肝脏有益。然而，如果铁过载与维生素E、硒的摄入失衡，这种保护作用可能减弱甚至逆转。
    • 铁与铜： 铁和铜在肝脏代谢中存在复杂的相互作用。铜是铁稳态的关键调节剂，参与铁的吸收、转运和储存。过量的铁可能影响铜的代谢，反之亦然。例如，在肝癌细胞中，铜水平升高，而EGCG（绿茶多酚）可通过螯合铜离子发挥促氧化作用，诱导DNA损伤，从而产生抗癌效果 76。这表明在特定情况下，矿物质间的平衡对维持肝脏细胞健康至关重要。

4.3.2 草药-维生素协同毒性

许多草药补剂含有丰富的植物化学物质，这些成分可能与维生素或矿物质发生复杂的相互作用，产生协同毒性，进一步增加肝脏负担。

  • 绿茶提取物与铁剂联合增加氧化应激： 绿茶提取物（GTE）富含儿茶素，特别是EGCG，具有强大的抗氧化活性。然而，在某些条件下，EGCG也可能表现出促氧化特性，尤其是在与铁结合时。研究表明，EGCG可以保护HepG2细胞免受CYP2E1依赖性毒性，这种毒性是由花生四烯酸（AA）和铁（Fe）诱导的 77。这表明EGCG可以对抗铁诱导的氧化应激，但高剂量的GTE与铁剂联合使用时，如果铁的螯合效应导致自由铁离子的释放增加，可能会产生协同的氧化应激，从而加重肝脏损伤。一些研究指出，GTE的肝毒性可能与个体差异及与其他成分的相互作用有关。

  • 草药成分与肝脏代谢酶的干扰： 许多草药成分能诱导或抑制肝脏的细胞色素P450（CYP）酶系统，从而影响其他药物或补剂的代谢。当草药与维生素或矿物质共同摄入时，如果草药成分干扰了维生素或矿物质的正常代谢途径，可能导致其在肝脏内的蓄积或产生毒性代谢产物。例如，一些草药补剂中的植物化学物质可以调节肠道和肝脏中的各种外源性酶和转运蛋白，从而影响微量营养素的吸收、分布、代谢和排泄 78。这种药草-微量营养素相互作用可能导致营养素缺乏，或者，在更少见的情况下，导致毒性，特别是当微量营养素以高剂量补充时。

  • 未知成分与非法添加： 复合补剂的成分复杂性还体现在其可能包含未明确标示的成分，甚至是非法添加的药物或有毒物质。这些“隐形”成分可能与补剂中已知的维生素或矿物质发生相互作用，产生意想不到的肝毒性。例如，一些减肥或增肌补剂可能非法添加西布曲明或合成类固醇，这些物质本身就具有潜在的肝毒性，若再与补剂中的其他成分相互作用，肝损伤的风险将显著增加。

综上所述，补剂成分的复杂性是导致肝损伤风险增加的一个重要方面。维生素-矿物质之间的平衡、草药成分与肝脏代谢酶的相互作用，以及潜在的协同毒性，都要求消费者和医疗专业人员在选择和使用复合补剂时保持高度警惕。对补剂进行全面成分分析和严格质量控制，以及个体化的风险评估，对于保障肝脏健康至关重要。

5. 临床证据与风险评估

补剂所致肝损伤（Supplement-induced Liver Injury, SLI）是药物性肝损伤（Drug-induced Liver Injury, DILI）的一个重要组成部分，其临床表现、流行病学特征、发生率及严重程度因补剂种类和个体差异而异。近年来，随着补剂使用量的激增，SLI的临床证据和研究也日益丰富，但仍面临诊断困难、数据不全等挑战。

流行病学数据：

DILI的流行病学数据在全球范围内存在差异，这主要与各国处方习惯、草药使用模式以及研究方法不同有关 73。

  • 中国： 一项在中国大陆进行的全国性回顾性研究，收集了2012年至2014年间25,927例确诊的DILI住院病例数据。结果显示，DILI的年发病率估计为23.8/10万人口（95% CI 20.86-26.74），高于西方国家报告的水平 79。在这项研究中，中草药或草药和膳食补充剂（Herbal and Dietary Supplements, HDS）是导致DILI的主要药物类别，占比高达26.81% 79。这表明HDS在中国DILI病因中占据突出地位，远超抗结核药物（21.99%）等传统药物 79。肝损伤类型以肝细胞损伤为主（51.39%），混合型（28.30%）和胆汁淤积型（20.31%）次之 79。在所有DILI病例中，13.00%发展为慢性DILI，有44.40%的肝细胞损伤病例符合Hy's Law标准，但进展为肝衰竭的比例较低（1.08%），死亡率仅为0.39% 79。
  • 全球趋势： 尽管DILI在普通人群中较为罕见，但在住院患者中，特别是那些有不明原因肝病史的患者中，其患病率更高 73。草药和膳食补充剂引起的肝毒性在全球范围内呈上升趋势 73。在美国，HDS已成为非对乙酰氨基酚相关DILI的主要原因 8081。一项基于美国国家健康和营养检查调查（NHANES）的调查研究显示，估计有1560万美国成年人（与服用非甾体抗炎药和常用降脂药的人数相当）在过去30天内使用过至少一种具有潜在肝毒性的植物产品 82。姜黄/姜黄素、绿茶提取物、藤黄果、黑升麻、红曲米和南非醉茄是被报道最多的肝毒性植物产品 82。
  • 性别差异： 研究表明，女性发生DILI的风险通常高于男性，比率为1.5至1.7倍，尤其是在49岁之后，更年期女性的易感性增加 83。这可能与药代动力学和药效学、性别特异性激素效应或免疫反应的差异有关 83。

随机对照试验（Randomized Controlled Trials, RCTs）证据：

  • 肌酸： 多项RCTs和荟萃分析表明，在健康人群中，短期（如5天）或长期（如5年）补充肌酸通常不会引起肝酶（ALT、AST）显著升高，对肝功能无明显负面影响。这支持了肌酸在健康个体中具有相对较好的肝脏安全性。然而，针对肝病患者的肌酸RCTs数据仍十分有限。
  • 益生菌与益生元： 益生菌和益生元在改善肝功能方面表现出一定的潜力，尤其是在NAFLD等疾病中。例如，一项研究发现，口服营养补充剂联合益生菌可以改善肺癌化疗患者的肝功能和肠道菌群状态，推测这可能与通过肠肝轴调节有关，表现为血清ALT、AST、内毒素水平的降低 84。另一项针对NAFLD患者的荟萃分析显示，水飞蓟素（一种常作为补剂使用的草药提取物）能显著降低ALT和AST水平，改善肝脏脂肪变性，提示其对肝脏的保护作用 85。然而，也有研究指出姜黄素补充剂联合生活方式干预在改善NAFLD患者的炎症指标和肝脏特征方面并不优于单独生活方式干预 86。
  • N-乙酰半胱氨酸（NAC）： NAC是一种常用的解毒剂，在某些肝损伤模型中显示出保护作用。例如，在梗阻性黄疸患者的旁路手术后，静脉注射NAC能显著保护肝功能，表现为术后血清AST、ALT、ALP、GGT和胆红素水平的降低 87。这表明NAC在特定情况下对肝脏具有保护潜力。

个案报告与Hy's法则：

个案报告是识别罕见或新发DILI的重要证据来源，而Hy's法则则是评估DILI严重性的关键标准。

  • Hy's法则： Hy's法则指的是在DILI诊断中，如果患者出现血清ALT或AST升高超过正常上限3倍，且总胆红素升高超过正常上限2倍，同时无胆汁淤积（如ALP升高不明显），则提示存在严重肝细胞损伤，预后可能较差，甚至有肝衰竭和死亡的风险 7980。符合Hy's法则的DILI病例通常被认为是更严重的肝损伤形式。
  • 绿茶提取物致急性肝衰竭： 绿茶提取物是导致SLI的常见原因之一。个案报告和系列研究显示，服用绿茶提取物，尤其是高剂量或与其他成分复方时，可能导致肝细胞性肝损伤，甚至急性肝衰竭。一项研究详细分析了美国DILI网络中的40例绿茶相关DILI病例，发现这些病例多表现为肝细胞损伤（95%），常伴有黄疸（83%），其中14例（35%）被评定为重度肝损伤，3例（8%）需要肝移植 88。该研究还发现，绿茶相关DILI与HLA-B*35:01基因型高度相关，提示其独特的免疫介导机制 88。
  • 传统中药引起的肝损伤： 传统中药或草药和膳食补充剂是导致中国DILI的主要药物类别之一 79。其临床表现多样，可为肝细胞性、胆汁淤积性或混合性肝损伤，严重时可导致急性肝衰竭。
  • 其他补剂相关DILI： 除了上述补剂，个案报告还揭示了其他多种补剂可能引发肝损伤。例如，左旋肉碱补剂曾被报道导致急性肝功能障碍。绿咖啡豆提取物也被报道引发急性肝衰竭。这些案例突出了补剂成分的复杂性及其潜在的肝毒性。
  • 抗生素相关DILI： 虽然本报告主要关注补剂，但值得注意的是，传统药物如抗生素也是DILI的重要原因。例如，头孢他啶（ceftazidime）和头孢吡肟（cefepime）等头孢类抗生素已被报道引起药物性肝损伤 8990。这些药物的DILI模式多为肝细胞性或混合性损伤，停药后通常可恢复。这提示我们在评估补剂肝毒性时，也需排除其他药物（包括处方药）的潜在影响。

风险评估的挑战：

补剂致肝损伤的诊断和风险评估面临多重挑战：

  1. 成分复杂性： 许多补剂，尤其是草药和复合补剂，成分复杂，活性物质含量不稳定，甚至可能存在非法添加或污染，难以准确评估其毒性。
  2. 监管不足： 许多国家对补剂的监管不如药品严格，上市前审批不充分，导致产品质量参差不齐，消费者信息不对称。
  3. 诊断困难： SLI的临床表现缺乏特异性，与其他肝病难以区分。此外，许多患者同时使用多种补剂和药物，增加了归因的难度。RUCAM（Roussel Uclaf Causality Assessment Method）评分工具常用于评估DILI的因果关系 91。
  4. 个体差异： 个体的遗传背景、年龄、性别 83、基础疾病和合并用药等因素均可能影响对补剂的反应，使得SLI的预测和预防更为复杂。

综上所述，临床证据表明，虽然许多补剂在适量使用下是安全的，但其潜在的肝损伤风险不容忽视，尤其是草药和复合补充剂。公众和临床医生都应提高警惕，谨慎使用补剂，并加强对SLI的监测和研究。

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参考文献

1A Global Overview of Dietary Supplements: Regulation, Market Trends, Usage during the COVID-19 Pandemic, and Health Effects.PubMed

Ouarda Djaoudene, Anabela Romano, Yasmine Djedjiga Bradai, et al.
Nutrients. 2023 Jul 26;15(15):3320. doi: 10.3390/nu15153320.
Over the last 20 years, the use of dietary supplements (DS) has continued to grow in many countries. Due to the public health crisis brought on by the COVID-19 pandemic and amidst fears regarding COVID-19 vaccines and their low supply in many regions of the world, there has been a marked interest in the use of DS as alternative means of protecting against and treating this emerging disease, as well as boosting the immune system and minimizing the risk of inflammation. Despite a lack of evidence to suggest their efficacy, a surge in the sales of DS has been reported in many parts of the world. Questions have also been raised about the health effects associated with DS due to their increased use during the health crisis. Numerous scientific studies have demonstrated their beneficial properties as well as some adverse and even toxic effects. In addition, given the current global interest in this issue, a review is needed to establish the status of dietary supplements before and during the health crisis. The aim of this review is to summarize the current evidence on the impact of dietary supplements on the incidence of the COVID-19 pandemic, as well as their regulation and associated market trends. First, we provide an overview of DS, including a comprehensive review of the legislative and regulatory aspects of DS in the USA, China, the EU, and Algeria. Second, we describe the prevalence of the most commonly consumed DS and their efficacy as a prophylactic modality in the era of COVID-19. Additionally, we examine the structure and size of the DS market in the countries that predominantly produce and import them, its global market trend, and the impact of the COVID-19 pandemic on market growth. Finally, in this review, we also discuss the profile of DS users.

2Trends in use of herbal and nutritional supplements in cardiovascular patients.PubMed

Tomasz Stys, Adam Stys, Patricia Kelly, et al.
Clin Cardiol. 2004 Feb;27(2):87-90. doi: 10.1002/clc.4960270208.
BACKGROUND: Use of herbs and nutritional supplements (known as naturoceuticals) is increasing in the USA, with about 50% of Americans taking naturoceuticals and spending over 10 billion dollars per year for them. This raises concerns regarding their use instead of proven therapies, their side effects, and drug interaction potential. HYPOTHESIS: The study sought to characterize cardiology patients who used supplements and to examine whether their use was diagnosis or doctor dependent, whether it affected patients' compliance, and what supplements were used. METHODS: In all, 187 patients attending our cardiology clinic were interviewed, examined, and followed for up to 1 year. The users and nonusers of naturoceuticals were compared. RESULTS: Supplements were used in 106 patients (an average of 3.1 naturoceutical per patient). There were no significant differences in their use by gender, age, primary care doctor specialty, or cardiovascular medications prescribed (except for statins). Patients with a history of myocardial infarction, coronary revascularization, hyperlipidemia, and a family history of coronary artery disease were more likely to use the supplements. Average low-density lipoprotein (106 vs. 108 mg/dl), average blood pressure (132/77 vs. 138/78 mmHg), and average hemoglobin (Hb)A1c (8.7 vs. 7.7%) showed no statistically significant differences between users and nonusers. Patients most commonly took multivitamins, vitamin E, vitamin C, vitamin B, folate, garlic, calcium, coenzyme Q10, and gingko. CONCLUSION: This study indicates that naturoceutical use is widespread among cardiovascular patients and it is difficult to predict clinically who the users are. Fortunately, according to our limited compliance measures, it appears that the naturoceutical use has not affected patients' compliance with traditional medications. Also, possibly a detrimental interaction potential between traditional medications and naturoceuticals has been demonstrated.

3Adverse Effects Associated with Multiple Categories of Dietary Supplements: The Military Dietary Supplement Use Study.PubMed

Joseph J Knapik, Daniel W Trone, Ryan A Steelman, et al.
J Acad Nutr Diet. 2022 Oct;122(10):1851-1863. doi: 10.1016/j.jand.2022.01.014. Epub 2022 Feb 2.
BACKGROUND: About 50% of Americans and 70% of US military service members (SMs) regularly use dietary supplements (DSs) and some are associated with adverse effects (AEs). SMs are more likely to use unsafe DSs than civilians. OBJECTIVE: The aim of this investigation was to examine the prevalence of, and factors associated with, AEs. DESIGN: Cross-sectional. PARTICIPANTS: A stratified random sample of 200,000 US SMs from the Air Force, Army, Marine Corps, and Navy were obtained from military workforce records. Eighteen percent (n = 26,681) of successfully contacted SMs (n = 146,365) volunteered to participate between December 2018 and August 2019. Participants completed a detailed online questionnaire on demographic characteristics, lifestyle factors, and AEs associated with DS use. MAIN OUTCOME MEASURE: Prevalence of, and factors associated with, AEs among DS users. STATISTICAL ANALYSIS: Prevalence of AEs was calculated by DS categories. Linear trends, χ statistics, and multivariable logistic regression examined associations between AEs and demographic characteristics, lifestyle factors, and number DSs consumed. RESULTS: Proportion of DS users (≥ 1 time /week) reporting ≥1 AE was 18% overall, 20% for combination products (ie, weight loss, muscle building, and before/after workout supplements), 8% for purported prohormones, 6% for protein/amino acid products, 6% for multivitamin/multiminerals, 6% for individual vitamins/minerals, 4% for herbal products, and 2% for joint health products. Combination products are very popular in military personnel with nearly half of SMs regularly taking them. In multivariable analysis, reporting AEs were independently associated with female gender, younger age, higher body mass index, smoking, higher alcohol intake, service in the Army, Navy, or Marine Corps (compared with Air Force), and consumption of a greater number of DSs. CONCLUSIONS: A large proportion of SMs report experiencing AEs, especially users of combination products and purported prohormone supplements. This study presents contemporary data collected from a very large at-risk population on potentially hazardous categories of DSs.

4Trends in Nutrient- and Non-Nutrient-Containing Dietary Supplement Use among US Children from 1999 to 2016.PubMed

Anita A Panjwani, Alexandra E Cowan, Shinyoung Jun, et al.
J Pediatr. 2021 Apr;231:131-140.e2. doi: 10.1016/j.jpeds.2020.12.021. Epub 2020 Dec 17.
OBJECTIVES: To characterize dietary supplement use among US children, including product type, motivations, user characteristics, and trends over time with a primary focus on non-vitamin/non-mineral dietary supplements (NVNM). STUDY DESIGN: Overall, NVNM, and vitamin and/or mineral dietary supplement only (VM-only) use; motivations for use; and trends in use over time were examined in children (≤19 years of age) using the National Health and Nutrition Examination Survey 1999-2016 data (n = 42 510). RESULTS: Between 1999 and 2016, overall dietary supplement and VM-only dietary supplement use among all children remained relatively stable at ∼30%; yet, NVNM dietary supplement use increased from 2.9% to 6.4%, mainly due to increased use of omega-3 polyunsaturated fatty acids. NVNM use was greater in boys than in girls (3.9% vs 3.3%), and greater in older children than in younger children (P < .0001), the opposite of what was observed with VM-only dietary supplement use. Although both user groups shared 2 primary motivations, both motivations were reported by a significantly greater percent of vitamin and/or mineral dietary supplement users vs NVNM users: to maintain health (38.7% vs 23.1%) and to improve health (33.1% vs 22.6%). NVNM users were much more likely to use dietary supplement for relaxation, stress, and sleep; for mental health; and for colon and bowel health. CONCLUSIONS: Although the prevalence of any dietary supplement and VM-only dietary supplement use among US children has both remained stable, the prevalence of NVNM use has increased substantially over time. Yet, NVNM use remains relatively low overall. NVNM use exhibited different patterns by sex, age, and motivations when compared with vitamin and/or mineral dietary supplement use. Despite increasing NVNM use, high-quality evidence supporting their use is lacking, especially in children.

5Botanicals and Hepatotoxicity.PubMed

Marina M Roytman, Peter Poerzgen, Victor Navarro
Clin Pharmacol Ther. 2018 Sep;104(3):458-469. doi: 10.1002/cpt.1097. Epub 2018 Jun 19.
The use of botanicals, often in the form of multi-ingredient herbal dietary supplements (HDS), has grown tremendously in the past three decades despite their unproven efficacy. This is paralleled by an increase in dietary supplement-related health complications, notably hepatotoxicity. This article reviews the demographics and motivations of dietary supplement (DS) consumers and the regulatory framework for DS in the US and other developed countries. It examines in detail three groups of multi-ingredient HDS associated with hepatotoxicity: OxyElite Pro (two formulations), green tea extract-based DS, and "designer anabolic steroids." These examples illustrate the difficulties in identifying and adjudicating causality of suspect compound(s) of multi-ingredient HDS-associated liver injury in the clinical setting. The article outlines future directions for further study of HDS-associated hepatotoxicity as well as measures to safeguard the consumer against it.

6Eight-Fold Increase in Dietary Supplement-Related Liver Failure Leading to Transplant Waitlisting Over the Last Quarter Century in the United States.PubMed

Marwan Ghabril, Jiayi Ma, Kavish R Patidar, et al.
Liver Transpl. 2022 Feb;28(2):169-179. doi: 10.1002/lt.26246. Epub 2021 Nov 27.
We investigated the trends in listing and outcomes of drug-induced acute liver failure (DIALF) over the last quarter century in the United States using the United Network for Organ Sharing (UNOS) database. We examined waitlisted patients in the UNOS database between 1995 and 2020 with a diagnosis of DIALF and assessed trends in etiologies, demographic and clinical characteristics, and outcomes over 3 periods: 1995-2003, 2004-2012, and 2013-2020. Patients with DIALF and cirrhosis were classified as drug-induced acute-on-chronic liver failure. Implicated agents including acetaminophen (APAP) and herbal or dietary supplements (HDSs) were ascertained. There were 2146 individuals with DIALF during the study period. The observed demographic trends between the earliest and latest period included fewer pediatric patients (18.8% to 13.5%) but with an increasing number of males in non-APAP DIALF (31.8% to 41.4%) and increased racial diversity in APAP DIALF. Antimicrobials remained the most common non-APAP agents across all periods, but antiepileptics, propylthiouracil, and mushroom poisoning decreased, while HDSs markedly increased from 2.9% to 24.1% of all non-APAP DIALF patients. The overall 5-year post-liver transplantation (LT) patient survival improved significantly over the 3 periods (69.9% to 77.4% to 83.3%) and was evident for both APAP and non-APAP DIALF. Over the last quarter century, there has been an 8-fold increase in HDS-related liver failure necessitating waitlisting for liver transplantation in the United States. There are other important temporal trends during the study period, including improved survival following LT among both APAP and non-APAP DIALF patients.

7Drug-induced liver injury in Australia, 2009-2020: the increasing proportion of non-paracetamol cases linked with herbal and dietary supplements.PubMed

Emily Nash, Abdul-Hamid Sabih, John Chetwood, et al.
Med J Aust. 2021 Sep 20;215(6):261-268. doi: 10.5694/mja2.51173. Epub 2021 Jul 17.
OBJECTIVE: To compare the characteristics and outcomes of drug-induced liver injury (DILI) caused by paracetamol and non-paracetamol medications, particularly herbal and dietary supplements. DESIGN: Retrospective electronic medical record data analysis. SETTING, PARTICIPANTS: Adults admitted with DILI to the Gastroenterology and Liver Centre at the Royal Prince Alfred Hospital, Sydney (a quaternary referral liver transplantation centre), 2009-2020. MAIN OUTCOME MEASURES: 90-day transplant-free survival; drugs implicated as causal agents in DILI. RESULTS: A total of 115 patients with paracetamol-related DILI and 69 with non-paracetamol DILI were admitted to our centre. The most frequently implicated non-paracetamol medications were antibiotics (19, 28%), herbal and dietary supplements (15, 22%), anti-tuberculosis medications (six, 9%), and anti-cancer medications (five, 7%). The number of non-paracetamol DILI admissions was similar across the study period, but the proportion linked with herbal and dietary supplements increased from 2 of 13 (15%) during 2009-11 to 9 of 19 (47%) during 2018-20 (linear trend: P = 0.011). Despite higher median baseline model for end-stage liver disease (MELD) scores, 90-day transplant-free survival for patients with paracetamol-related DILI was higher than for patients with non-paracetamol DILI (86%; 95% CI, 79-93% v 71%; 95% CI, 60-82%) and herbal and dietary supplement-related cases (59%; 95% CI, 34-85%). MELD score was an independent predictor of poorer 90-day transplant-free survival in both paracetamol-related (per point increase: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.09-3.74) and non-paracetamol DILI (aHR, 1.24; 95% CI, 1.14-1.36). CONCLUSION: In our single centre study, the proportion of cases of people hospitalised with DILI linked with herbal and dietary supplements has increased since 2009. Ninety-day transplant-free survival for patients with non-paracetamol DILI, especially those with supplement-related DILI, is poorer than for those with paracetamol-related DILI.

8Potential cytochrome P450-mediated pharmacokinetic interactions between herbs, food, and dietary supplements and cancer treatments.PubMed

Paul Gougis, Marc Hilmi, Arthur Geraud, et al.
Crit Rev Oncol Hematol. 2021 Oct;166:103342. doi: 10.1016/j.critrevonc.2021.103342. Epub 2021 Apr 28.
Herbs, food and dietary supplements (HFDS), can interact significantly with anticancer drug treatments via cytochrome p450 isoforms (CYP) CYP3A4, CYP2D6, CYP1A2, and CYP2C8. The objective of this review was to assess the influence of HFDS compounds on these cytochromes. Interactions with CYP activities were searched for 189 herbs and food products, 72 dietary supplements in Web of Knowledge® databases. Analyses were made from 140 of 3125 clinical trials and 236 of 3374 in vitro, animal model studies or case reports. 18 trials were found to report direct interactions between 9 HFDS with 8 anticancer drugs. 21 HFDS were found to interact with CYP3A4, a major metabolic pathway for many anticancer drugs. All 261 HFDS were classified for their interaction with the main cytochromes P450 involved in the metabolism of anticancer drugs. We provided an easy-to-use colour-coded table to easily match potential interactions between 261 HFDS and 117 anticancer drugs.

9Ashwagandha () Plant Extracts Affect the Cytochrome P450 System and Cytotoxicity of Primary Human Hepatocytes.PubMed

Kelli L McDonald, Zarna Raichura, Satyanarayana R Pondugula, et al.
J Diet Suppl. 2025;22(4):613-639. doi: 10.1080/19390211.2025.2514458. Epub 2025 Jun 24.
Ashwagandha ( [L] Dunal) is emerging as one of the top 10 botanicals in the market due to its claimed health benefits as an adaptogen. Alongside its popularity, the lack of standardization in botanical dietary supplements and potential interactions with prescription drugs raise safety concerns. This study aimed to investigate the potential of ashwagandha extracts to induce cytochrome P450 (P450) enzymes, which are critical for drug metabolism and implicated in botanical-drug interactions. A sandwich-cultured in vitro assay using primary human hepatocytes was utilized to evaluate the induction potential of aqueous and 70% ethanolic extracts of ashwagandha roots and leaves on CYP3A4, CYP2B6, and CYP1A2-enzymes commonly involved in drug metabolism. Unlike prior studies that focused on root extracts or used HepG2 cell lines, this research included both root and leaf plant extracts, with the latter being assessed for the first time. Our approach using primary hepatocytes enhances clinical relevance compared to other in vitro models (such as HepG2 cell lines). Additionally, cytotoxicity was examined using CellTitre-Glo Luminescent Assay, measuring cell viability at three different incubation times (24, 48, and 72 hours) to assess the potential cytotoxic effect of the ashwagandha plant extracts. Our findings revealed that 70% ethanol ashwagandha root extracts (WSR-2) modulated CYP3A4 enzyme expression and activity. Preliminary studies on cytotoxicity indicated dose- and time-dependent impact on hepatocyte viability with a high concentration of 70% ethanol ashwagandha leaf extracts (WSL-2). The study highlights the importance of understanding ashwagandha's impact on P450-based drug metabolism and its safe co-administration with prescribed drugs.

10Evaluation of reversible cytochrome P450 inhibition by Withania somnifera leaf and root extracts.PubMed

Zarna Raichura, Kabre Heck, Jaewoo Choi, et al.
Drug Metab Dispos. 2025 Feb;53(2):100024. doi: 10.1016/j.dmd.2024.100024. Epub 2024 Nov 29.
It is important to understand the potential of botanical-drug interactions to ensure the safe use of botanical dietary supplements (BDS). Cytochrome P450 (P450) is one of the most abundant phase 1 drug-metabolizing enzymes and is accountable for a great deal of pharmacokinetic botanical-drug interactions. This problem is particularly acute for older adults who often consume BDS with multiple prescription medicines. The consequences of botanical-drug interactions can lead to lack of prodrug efficacy or drug toxicity from reduced drug clearance through inhibition of P450 metabolizing enzymes. In this study, a 7-in-1 cocktail P450 inhibition assay with 7 Food and Drug Administration-recommended P450s (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4/5) including CYP2B6 recombinant enzyme was performed, minimizing substrate interactions with respect to specificity while maximizing assay sensitivity. High-performance liquid chromatography-mass spectrometry was used for quantitative determination of probe substrate metabolism. Withania somnifera L. Dunal (ashwagandha), a popular BDS in the United States with sales of ∼$16 million in 2021, is used to promote sleep and relieve stress and anxiety, especially in older adults. However, comprehensive studies of pharmacokinetic drug interactions with ashwagandha, especially with leaf extracts, have not been reported. Four extracts from ashwagandha root or leaf were evaluated for P450 inhibition, and no reversible inhibition was detected at IC > 100 μg/mL extract. SIGNIFICANCE STATEMENT: Ashwagandha is often consumed by older adults, who also often use multiple prescribed medications concomitantly. Polypharmacy, combined with age-related decline of drug metabolism and other changes in drug disposition in this population, increases the risk of adverse events due to botanical inhibition of drug metabolism, indicating the significance of evaluating ashwagandha for potential pharmacokinetic drug interactions. This study will support our understanding for the safe use of ashwagandha.

11PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases.PubMed

Gina M Gallucci, Colleen M Hayes, James L Boyer, et al.
Cells. 2024 Aug 1;13(15):1296. doi: 10.3390/cells13151296.
Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, β/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (β/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.

12[MALABSORPTION FAT-SOLUBLE VITAMINS AND PROSPECTS OF THEIR USE IN LIVER DISEASES].PubMed

A I Khavkin, O N Komarova
Eksp Klin Gastroenterol. 2016(7):86-94.
In a review article considers issues of efficiency and tactics of the purpose of fat-soluble vitamins, as in cholestatic and noncholestatic liver disease, as well as water-soluble vitamins, particularly vitamin C cholelithiasis. Oxidative stress due to chronic inflammation is one of the major conversion mechanisms of liver fibrosis in cirrhosis. The imbalance between production of reactive oxygen species and antioxidant defense causes a number of pathophysiological changes in the liver, including activation of hepatic stellate cells. The carriers of the I148M PNPLA3 mutation was not observed concentration reduction in liver vitamin A with increasing severity of the disease, but the observed decrease in the level of circulating retinyl palmitate and retinol-binding protein. To the appointment of vitamin A in liver disease should be approached with caution. Hypervitaminosis A leads to accelerated liver fibrosis and stimulates carcinogenesis. Currently actively studied the possibility of using vitamin E as an antioxidant, in patients with non-alcoholic fatty liver disease. His presence in the membranes phospholipid bilayer allows cells to prevent non-enzymatic oxidation of cell components by free radicals. Vitamin E can suppress the profibrotic processes. In patients with chronic cholestatic liver disease is common, vitamin K deficiency, even when administered, and is associated with the degree of cholestasis and severity of disease. The vitamin D deficiency, liver disease is also associated with the severity of disease correlated with the severity of liver failure and infectious complications. Vitamin D is an independent prognostic parameter for mortality risk in patients with liver cirrhosis.

13Bile acid signaling in metabolic disease and drug therapy.PubMed

Tiangang Li, John Y L Chiang
Pharmacol Rev. 2014 Oct;66(4):948-83. doi: 10.1124/pr.113.008201.
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid-activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein-coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver.

14Fat-Soluble Vitamins Deficiency in Pediatric Cholestasis: A Scoping Review.PubMed

Irene Degrassi, Ilaria Leonardi, Elisabetta Di Profio, et al.
Nutrients. 2023 May 26;15(11):2491. doi: 10.3390/nu15112491.
BACKGROUND: This review aims to identify the current indications and gaps in the management of fat-soluble vitamins in pediatric patients with cholestasis. METHODS: A comprehensive review of the literature using PubMed, Scopus, Web of Science and Embase was performed. Two authors independently identified the most relevant studies published over the past 20 years up to February 2022, including original papers, narrative reviews, observational studies, clinical trials, systematic reviews and meta-analyses. The literature was screened, and preclinical studies about pathogenetic mechanisms were also included. Keywords searched for each fat-soluble vitamin (A, D, E and K), alone or in combination, were "cholestasis", "chronic liver disease", "biliary atresia", "malnutrition" and "nutritional needs". Studies published prior to the selected time range were searched manually and, when considered relevant, included within the list of references. RESULTS: Eight hundred twenty-six articles were initially screened. From these, 48 studies were selected. A comparison of the recommended methods of supplementation for fat-soluble vitamins was then carried out. The causes of malabsorption were explained and current methods for defining deficiency and monitoring complications were summarized. CONCLUSIONS: According to the literature, children with cholestasis are at a higher risk of fat-soluble vitamin deficiency. Although there are general recommendations, the treatment for vitamin deficiency is not uniformly validated.

15Secondary Malnutrition and Nutritional Intervention in Cholestatic Liver Diseases in Infants.PubMed

Alfredo Larrosa-Haro, Erika A Caro-Sabido
Front Nutr. 2021 Nov 15;8:716613. doi: 10.3389/fnut.2021.716613. eCollection 2021.
We aimed to conduct an updated review on the pathophysiology, diagnosis, and nutritional intervention of CCLD and secondary malnutrition in infants. Protein-energy malnutrition, impaired linear growth, fat-soluble vitamin deficiencies, and hepatic osteodystrophy can occur in up to 80% of cases. The proposed pathophysiological mechanisms include insufficient energy intake, lipid- and fat-soluble vitamin malabsorption, increased energy expenditure, altered intermediate metabolism, hormonal dysregulation, and systemic inflammation. The current approach to diagnosis is the identification of the deviation of growth parameters, body composition, and serum concentration of micronutrients, which determines the type and magnitude of malnutrition. Currently, liver transplantation is the best therapeutic alternative for the reversal of nutritional impairment. Early and effective portoenteroanatomosis can extend survival in patients with biliary atresia. Medical and dietary interventions in some storage and metabolic diseases can improve liver damage and thus the nutritional status. A proportion of patients with biliary atresia have fat-soluble vitamin deficiencies despite receiving these vitamins in a water-soluble form. With aggressive enteral nutrition, it may be possible to increase fat stores and preserve muscle mass and growth. The nutritional issues identified in the pre- and post-transplantation stages include muscle mass loss, bone demineralization, growth retardation, and obesity, which seems to correspond to the natural history of CCLD. Due to the implications for the growth and development of infants with CCLD with this complex malnutrition syndrome, innovative projects are required, such as the generation of prediction and risk models, biomarkers of growth and body composition, and effective strategies for nutritional prevention and intervention.

16Selenomethionine supplementation mitigates fluoride-induced liver apoptosis and inflammatory reactions by blocking Parkin-mediated mitophagy in mice.PubMed

Tianyu Wang, Haojei Li, Yuanyuan Li, et al.
Sci Total Environ. 2024 Nov 15;951:175458. doi: 10.1016/j.scitotenv.2024.175458. Epub 2024 Aug 12.
As an environmental pollutant, fluoride-induced liver damage is directly linked to mitochondrial alteration and oxidative stress. Selenium's antioxidant capacity has been shown to alleviate liver damage. Emerging research proves that E3 ubiquitin ligase Park2 (Parkin)-mediated mitophagy may be a therapeutic target for fluorosis. The current study explored the effect of diverse selenium sources on fluoride-caused liver injury and the role of Parkin-mediated mitophagy in this intervention process. Therefore, this study established a fluoride-different selenium sources co-intervention wild-type (WT) mouse model and a fluoride-optimum selenium sources co-intervention Parkin gene knockout (Parkin-/-) mouse model. Our results show that selenomethionine (SeMet) is the optimum selenium supplementation form for mice suffering from fluorosis when compared to sodium selenite and chitosan nano‑selenium because mice from the F-SeMet group showed more closely normal growth and development levels of liver function, antioxidant capacity, and anti-inflammatory ability. Explicitly, SeMet ameliorated liver inflammation and cell apoptosis in fluoride-toxic mice, accomplished through downregulating the mRNA and protein expression levels associated with mitochondrial fusion and fission, mitophagy, apoptosis, inflammatory signalling pathway of nuclear factor-kappa B (NF-κB), reducing the protein expression levels of PARKIN, PTEN-induced putative kinase1 (PINK1), SQSTM1/p62 (P62), microtubule-associated protein light chain 3 (LC3), cysteinyl aspartate specific proteinase 3 (CASPAS3), as well as restraining the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ). The Parkin-/- showed comparable positive effects to the SeMet in the liver of fluorosis mice. The structure of the mitochondria, mRNA, protein expression levels, and the content of proinflammatory factors in mice from the F and F + SeMet groups closely resembled those in the F + SeMet group. Overall, the above results indicated that SeMet could alleviate fluoride-triggered inflammation and apoptosis in mice liver via blocking Parkin-mediated mitophagy.

17[Elastosis perforans serpiginosa with vitamin A deficiency in a child with trisomy 21].PubMed

V Jan, J Saugier, B Arbeille, et al.
Ann Dermatol Venereol. 1996;123(3):188-90.
INTRODUCTION: Elastosis perforans serpiginosa frequently occurs in trisomy 21. Usually no cause is found. We report a case in which vitamin deficiency may have contributed to the development of skin lesions. CASE REPORT: A 11-year-old girl with trisomy 21 developed papulokeratosic eruptions with a linear serpiginous distribution, predominantly involving the lower limbs. On ultrastructure examination, numerous elastic fibers penetrated the epiderma and the baseline membrane had disappeared. The patient also had a totally patent atrioventricular canal with hypoplasia of the left ventricle and cardiac liver. Serum vitamin A level was low (0.56 mumol/l, normal > 1.55). Acitretine was prescribed at the dose of 0.5 mg/kg/day but had to be stopped 2 months later due to elevated liver enzyme levels despite a clear clinical improvement. DISCUSSION: This association between elastosis perforans serpiginosa and vitamin A deficiency, observed here in a child with trisomy 21, has never been reported by others. Vitamin A deficiency might aggravate the skin lesions. In our case, there was probably a relationship between the vitamin A deficiency and the cardiogenic liver disease. The keratoregulatory effect of vitamin A on elastic tissue is less well known. Treatment with retinoids provided clinical improvement but had to be stopped due to hepatotoxicity. Parenteral vitamin A would be an interesting alternative but the risk of side effects would theoretically be greater than with oral retinoids.

18Vitamin D receptor attenuates carbon tetrachloride-induced liver fibrosis via downregulation of YAP.PubMed

Ping Wang, Jie Li, Mintao Ji, et al.
J Hazard Mater. 2024 Oct 5;478:135480. doi: 10.1016/j.jhazmat.2024.135480. Epub 2024 Aug 10.
Liver fibrosis is characterized by the excessive accumulation of extracellular matrix proteins, which can lead to cirrhosis and liver cancer. Metabolic dysfunction-associated steatosis liver diseases are common causes of liver fibrosis, sharing a similar pathogenesis with carbon tetrachloride (CCl₄) exposure. This process involves the activation of hepatic stellate cells (HSCs) into myofibroblasts. However, the detailed mechanism and effective treatment strategies require further investigation. In this study, we uncovered a negative correlation between VDR expression and YAP within HSCs. Subsequently, we demonstrated that VDR exerted a downregulatory influence on YAP transcriptional activity in HSCs. Intriguingly, activation VDR effectively inhibited the culture induced activation of primary HSCs by suppressing the transcriptional activity of early YAP. Furthermore, in vivo results manifested that hepatic-specific deletion of YAP/TAZ ameliorates CCl-induced liver fibrosis, and nullified the antifibrotic efficacy of VDR. Importantly, a YAP inhibitor rescued the exacerbation of liver fibrosis induced by hepatic-specific VDR knockout. Moreover, the combined pharmacological of VDR agonist and YAP inhibitor demonstrated a synergistic effect in diminishing CCl-induced liver fibrosis, primary HSCs activation and hepatic injury in vivo. These effects were underpinned by their collective ability to inhibit HSC activation through AMPK activation, consequently curbing ATP synthesis and HSCs proliferation. In conclusion, our results not only revealed the inhibition of VDR on YAP-activated liver stellate cells but also identified a synergistic effect of VDR agonist and YAP inhibitor in an AMPKα-dependent manner, providing a practical foundation for integration of multi-targeted drugs in the therapy of CCl-induced hepatic fibrosis.

19Vitamin D 1,25-Dihydroxyvitamin D reduces lipid accumulation in hepatocytes by inhibiting M1 macrophage polarization.PubMed

Wen-Jing Luo, Xian-Wen Dong, Hua Ye, et al.
World J Gastrointest Oncol. 2024 Dec 15;16(12):4685-4699. doi: 10.4251/wjgo.v16.i12.4685.
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), which is a significant liver condition associated with metabolic syndrome, is the leading cause of liver diseases globally and its prevalence is on the rise in most nations. The protective impact of vitamin D on NAFLD and its specific mechanism remains unclear. AIM: To examine the role of vitamin D in NAFLD and how vitamin D affects the polarization of hepatic macrophages in NAFLD through the vitamin D receptor (VDR)-peroxisome proliferator activated receptor (PPAR)γ pathway. METHODS: Wild-type C57BL/6 mice were provided with a high-fat diet to trigger NAFLD model and administered 1,25-dihydroxy-vitamin D [1,25(OH)D] supplementation. 1,25(OH)D was given to RAW264.7 macrophages that had been treated with lipid, and a co-culture with AML12 hepatocytes was set up. Lipid accumulation, lipid metabolism enzymes, M1/M2 phenotype markers, proinflammatory cytokines and VDR-PPARγ pathway were determined. RESULTS: Supplementation with 1,25(OH)D relieved hepatic steatosis and decreased the proinflammatory M1 polarization of hepatic macrophages in NAFLD. Administration of 1,25(OH)D suppressed the proinflammatory M1 polarization of macrophages induced by fatty acids, thereby directly relieving lipid accumulation and metabolism in hepatocytes. The VDR-PPARγ pathway had a notable impact on reversing lipid-induced proinflammatory M1 polarization of macrophages regulated by the administration of 1,25(OH)D. CONCLUSION: Supplementation with 1,25(OH)D improved hepatic steatosis and lipid metabolism in NAFLD, linked to its capacity to reverse the proinflammatory M1 polarization of hepatic macrophages, partially by regulating the VDR-PPARγ pathway. The involvement of 1,25(OH)D in inhibiting fatty-acid-induced proinflammatory M1 polarization of macrophages played a direct role in relieving lipid accumulation and metabolism in hepatocytes.

20Fat-soluble vitamin deficiency in infants and children.PubMed

E A Argao, J E Heubi
Curr Opin Pediatr. 1993 Oct;5(5):562-6. doi: 10.1097/00008480-199310000-00008.
Fat-soluble vitamin deficiency is known to result in various complications that may be prevented if the problem is recognized and managed appropriately. In infants and children with chronic cholestasis, replacement therapy of the fat-soluble vitamins, vitamins A, D, E, and K, may prove extremely difficult because low concentrations of intraluminal bile acids lead to malabsorption of these compounds and other fat-soluble substances. Recent progress in the use of a water-soluble form of vitamin E, d-alpha-tocopheryl polyethylene glycol-1000 succinate, has enabled correction of vitamin E-deficiency states in these patients. It has also allowed for the admixture and coadministration of other fat-soluble vitamins and compounds in d-alpha-tocopheryl polyethylene glycol-1000 succinate to enhance their absorption. For managing vitamin K deficiency, similar success has been achieved using a vitamin K compound solubilized in glycocholate and lecithin. Vitamin A deficiency has been implicated in the higher incidence of childhood mortality and morbidity in Third World countries. Increased risk of childhood cancer has recently been associated with intramuscular injection of vitamin K to newborns. Finally, it is worth noting that among the pediatric population, exclusively breastfed infants, in general, are at risk for hypovitaminosis D, and at even greater risk in the absence of adequate exposure to sunlight or when the maternal diet is not sufficient to provide for vitamin D requirements.

21Treatment Options for Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis.PubMed

Cynthia Levy, Keith D. Lindor
Curr Treat Options Gastroenterol. 2003 Apr;6(2):93-103. doi: 10.1007/s11938-003-0010-0.
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases that affect 0.5 to 40 per 100,000 and 1 to 6 per 100,000 Americans, respectively. Prompt recognition and management of the clinical manifestations of these diseases is essential for the patients' well-being and ultimate outcome. Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg per day, is the standard therapy for PBC and should be offered to every patient. It has been shown to slow progression of the disease and prevent the need for liver transplantation, which is the last recourse for patients with end-stage disease. However, there is no effective therapy for PSC yet. Patients are managed symptomatically, with surgical or endoscopic interventions as needed in cases of significant biliary obstruction. Complications of chronic cholestasis are seen in both PBC and PSC, with pruritus and fatigue being the most common complaints. The first choice for the treatment of pruritus is still cholestyramine, starting at 4 g/d. The pathogenesis of fatigue is poorly understood in this population; unrecognized hypothyroidism should be excluded. The use of antidepressants is currently under evaluation, but there is no specific therapy for fatigue as of yet. For prevention of severe osteoporosis, we recommend supplementation with 800 IU vitamin D and 1500 mg calcium/d. In patients with PBC and established osteoporosis, the use of alendronate and vitamin K appears to cause an increase in bone mineral density. Further studies are necessary before either of these drugs is routinely recommended. Finally, fat-soluble vitamin deficiencies are noted with more advanced disease. We recommend that serum levels be checked in high-risk patients, and that vitamins are replaced as appropriate with water-soluble supplements. However, other causes of malabsorption must be ruled out, including pancreatic insufficiency and celiac sprue.

22Effect of hydrosoluble vitamin E on erythrocyte membrane lipid composition in patients with advanced cirrhosis: An open-label pilot trial.PubMed

Sophie Restellini, Mahnaz Alaei, Thomas Matthes, et al.
Hepatol Res. 2015 Aug;45(8):890-7. doi: 10.1111/hepr.12430. Epub 2014 Dec 2.
AIM: Deficiency in vitamin E, a natural antioxidant, participates in abnormal erythrocyte membrane lipids, structural alterations and hemolysis in advanced cirrhosis. Poor absorption of fat-soluble vitamins limits full correction of deficiency with standard formulations in cirrhosis with cholestasis. The aim of the present study was to examine safety and effects of tocofersolan, a water-soluble derivative of vitamin E, on erythrocyte membrane lipids and anemia in patients with biopsy-proven advanced cirrhosis, vitamin E deficiency and hemolysis. METHODS: Twenty patients (age, 53 ± 10 years; Child class B/C, 8/12), with low plasma vitamin E, chronic anemia and hemolysis, received oral tocofersolan 700 mg/day for 4 weeks. Erythrocyte membrane lipid composition (cholesterol [Chol], phospholipids [Phosph]) was determined by enzymatic assays. Total and conjugated bilirubin, hemoglobin and vitamin E were measured. RESULTS: Abdominal pain occurred in one patient. Five patients received blood transfusions due to severe anemia. After 4 weeks, both Chol and Phosph decreased, but changes were not significant. Both plasma vitamin E (P < 0.05) and hemoglobin (P < 0.05) increased, together with a decrease in total (P < 0.05) and conjugated (P < 0.05) bilirubin. CONCLUSION: In patients with advanced cirrhosis, low vitamin E plasma levels and chronic anemia with hemolysis, oral tocofersolan was overall well tolerated, but did not affect erythrocyte membrane lipid composition.

23Safety evaluation of rare ginsenosides of stems and leaves from American ginseng: 90-day exposure toxicity study combined with intestinal flora analysis and metabonomics in rats.PubMed

Yuqing Cao, Feiyan Tao, Yuan Yu, et al.
Ecotoxicol Environ Saf. 2023 Oct 1;264:115429. doi: 10.1016/j.ecoenv.2023.115429. Epub 2023 Sep 5.
Rare ginsenosides have already been widely applied in many fields, including health food and bio-medicine. The human being can expose to rare ginsenosides directly or indirectly increasingly. However, there are few studies on the safety assessment of rare ginsenoside mixtures. In the present study, the sub-chronic toxicity of rare ginsenosides for 90 days on SD rats was performed by combining the intestinal flora analysis and urine metabonomics aiming to illustrate the safety of long-term consumption of rare ginsenosides and the potential damage for liver and intestinal. 48 adult rats were divided into four groups: control (0 mg/kg), low-dose (60 mg/kg), medium-dose (200 mg/kg), and high-dose (600 mg/kg). Rats in the high-dose group showed inflammatory changes in their livers and intestines. The strong bactericidal effect of rare ginsenosides caused intestinal flora disorder and changed the structure of intestinal flora in rats, thus inducing intestinal damage in rats. In the high-dose group, levels of alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and alkaline phosphatase (AKP) increased significantly. As a result of the high-dose treatment, certain metabolic pathways were altered, such as vitamin B6 metabolism, methionine metabolism, glutathione metabolism, and others. These results indicated that high doses of rare ginsenosides induced liver injury by affecting the above metabolic pathways. Rare ginsenosides with no observed adverse effect level (NOAEL) were below 200 mg/kg/day in vivo. Thus, this present study provides insight into the rational use of rare ginsenosides.

24Antioxidative stress effects of vitamins C, E, and B, and their combination can protect the liver against acetaminophen-induced hepatotoxicity in rats.PubMed

Farah M Abdulkhaleq, Tawfiq M Alhussainy, Mujtaba M Badr, et al.
Drug Des Devel Ther. 2018 Oct 18;12:3525-3533. doi: 10.2147/DDDT.S172487. eCollection 2018.
BACKGROUND: Several vitamins, including C, E, and B, have been recognized as antioxidants and have shown hepatoprotective effects against the hepatotoxicity caused by acetaminophen (APAP) overdose. The current investigation aims to study the effect of these vitamins and their combination in protecting the liver from APAP hepatotoxicity in rats. MATERIALS AND METHODS: An in vitro model of freshly isolated rat hepatocytes was utilized for assessing hepatocyte mitochondrial activity conducted by cell proliferation assay (MTT). The isolated hepatocytes were treated with vitamin C, vitamin E, vitamin B and their combination, with and without further addition of toxic concentrations of APAP. In addition, an in vivo experiment was carried out on Sprague Dawley rats treated intraperitoneally for 8 days with emulsions of the vitamins or their combination prior to injecting them with APAP. RESULTS: In vitro results showed that vitamins C and B and the combination preparation significantly increased the percentage of hepatocyte mitochondrial activity, both with and without the addition of APAP (<0.01). The mitochondrial activity in the isolated cultured hepatocytes was further enhanced with APAP addition. In vivo, the vitamins and their combination effectively reduced APAP-induced serum liver enzymes levels, namely ALT, AST, and ALP, and also attenuated oxidative stress and lipids peroxidation confirmed by the results of glutathione, superoxide dismutase, and maloondialdehyde. CONCLUSION: Pretreatment with vitamins C, E, B, or their combination was found to be beneficial in preventing in vivo hepatic oxidative stress induced by APAP overdose. Vitamin C on its own showed superior protection against APAP-induced liver injury in rats compared to the other vitamins. The proliferation of APAP-intoxicated liver cells in vitro was highest when protected with the vitamins' combination.

25Iron loading exerts synergistic action via a different mechanistic pathway from that of acetaminophen-induced hepatic injury in mice.PubMed

Gyul Moon, Sho Kobayashi, Ye Aung Naing, et al.
Free Radic Res. 2020 Sep;54(8-9):606-619. doi: 10.1080/10715762.2020.1819996. Epub 2020 Sep 28.
Acetaminophen (APAP) overdose is a major cause of drug-induced acute liver failure. In such cases, free iron is released from lysosomes and is transported to mitochondria where it plays a pivotal role in APAP-induced liver injury. We previously reported that ascorbic acid (Asc) markedly mitigates APAP-induced hepatic damage in aldehyde reductase (Akr1a)-knockout (KO) mice that produce about 10% Asc as wild-type (WT) mice. However, the issue of the protective mechanism of Asc in association with the status of iron remains ambiguous. To gain additional insights into this issue, we examined effects of APAP (500 mg/kg) on female KO mice under conditions of iron loading. While the KO mice without AsA supplementation were more sensitive to APAP toxicity than the WT mice, FeSO loading (25 mg/kg) to WT mice aggravated the hepatic injury, which was a similar extent to that of the KO mice. Supplementation of Asc (1.5 mg/ml in the drinking water) ameliorated KO mice irrespective of iron status but did not change the iron-mediated increase in the lethality in the WT mice. Hepatic cysteine and glutathione levels declined to similar extents in all mouse groups at 3 h irrespective of the iron status and largely recovered at 18 h after the APAP treatment when liver damage was evident. Asc prominently mitigated APAP toxicity in KO mice irrespective of the iron status but had no effect on the synergistic action of iron and APAP in the WT mice, suggesting that the mechanism for the deteriorating action of loaded iron is different from that of APAP toxicity.

26Coenzyme Q and Selenium Co-Supplementation Alleviate Methionine Choline-Deficient Diet-Induced Metabolic Dysfunction-Associated Steatohepatitis in Mice.PubMed

Hyewon Choi, Jiwon Choi, Yula Go, et al.
Nutrients. 2025 Jan 9;17(2):229. doi: 10.3390/nu17020229.
BACKGROUND/OBJECTIVES: The pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) is closely associated with increased oxidative stress and lipid peroxidation. Coenzyme Q (CoQ) and selenium (Se) are well-established antioxidants with protective effects against oxidative damage. This study aimed to investigate the effects of CoQ and Se in ameliorating MASH induced by a methionine choline-deficient (MCD) diet in mice. METHODS: C57BL/6J male mice were fed either a methionine choline-sufficient (MCS) or MCD diet and treated with vehicle, CoQ (100 mg/kg), Se (158 μg/kg), or their combination (CoQ + Se) for 4 weeks. RESULTS: The MCD diet significantly increased hepatic steatosis, inflammation, and fibrosis compared to MCS controls. Treatment with CoQ and Se, particularly in combination, markedly reduced the MAFLD activity score, hepatic inflammation, and fibrosis. Combined supplementation of CoQ and Se significantly decreased serum alanine aminotransferase and aspartate aminotransferase levels and hepatic TG and cholesterol concentrations. CoQ and Se effectively mitigated hepatic oxidative stress by enhancing catalase and superoxide dismutase activities, increasing glutathione peroxidase (GPX) activity, and restoring the GSH/GSSG ratio. Lipid peroxidation markers, such as malondialdehyde and 4-hydroxynonenal, were significantly reduced. Furthermore, the expression of ferroptosis-related markers, including acyl-CoA synthetase long-chain family member 4, arachidonate 12-lipoxygenase, and hepatic non-heme iron content, was significantly downregulated, while GPX4 expression was upregulated by combined CoQ and Se treatment. CONCLUSIONS: CoQ and Se synergistically alleviate MASH progression by reducing oxidative stress and lipid peroxidation, which may contribute to the suppression of ferroptosis. Combined CoQ and Se supplementation demonstrates therapeutic potential for managing MASH and related liver injury.

27Protective effects and mechanism of chemical- and plant-based selenocystine against cadmium-induced liver damage.PubMed

Lin Zhang, Wen-Yao Shi, Jia-Ying Xu, et al.
J Hazard Mater. 2024 Apr 15;468:133812. doi: 10.1016/j.jhazmat.2024.133812. Epub 2024 Feb 16.
Although selenium (Se) and cadmium (Cd) often coexist naturally in the soil of China, the health risks to local residents consuming Se-Cd co-enriched foods are unknown. In the present study, we investigated the effects of chemical-based selenocystine (SeCys) on cadmium chloride-induced human hepatocarcinoma (HepG2) cell injury and plant (Cardamine hupingshanensis)-derived SeCys against Cd-induced liver injury in mice. We found that chemical- and plant-based SeCys showed protective effects against Cd-induced HepG2 cell injury and liver damage in mice, respectively. Compared with Cd intervention group, co-treatment with chemical- or plant-based SeCys both alleviated liver toxicity and ferroptosis by decreasing ferrous iron, acyl-CoA synthetase long-chain (ACSL) family member 4, lysophosphatidylcholine acyltransferase 3, reactive oxygen species and lipid peroxide levels, and increasing ACSL3, peroxisome proliferator-activated receptor α, solute carrier family 7 member 11 (SLC7A11) and glutathione and glutathione peroxidase 4 (GPX4) levels. In conclusion, chemical- and plant-based SeCys alleviated Cd-induced hepatotoxicity and ferroptosis by regulating SLC7A11/GPX4 signaling and lipid peroxidation. Our findings indicate that potential Cd toxicity from consuming foods grown in Se- and Cd-rich soils should be re-evaluated. This study offers a new perspective for the development of SeCys-enriched agricultural products.

28Nano-Selenium Alleviates Cadmium-Induced Acute Hepatic Toxicity by Decreasing Oxidative Stress and Activating the Nrf2 Pathway in Male Kunming Mice.PubMed

Hong Du, Yilei Zheng, Wei Zhang, et al.
Front Vet Sci. 2022 Jul 26;9:942189. doi: 10.3389/fvets.2022.942189. eCollection 2022.
Cadmium (Cd) is known as a highly toxic heavy metal and has been reported to induce hepatotoxicity in animals. Nano-selenium (NSe) is an antioxidant that plays many biological roles such as oxidative stress alleviation. The purpose of this study is to explore the mechanism of action by which NSe inhibits Cd-induced hepatic toxicity and oxidative stress. Sixty eight-week-old male Kunming mice were randomly divided into four groups (15 mice per group). The control group and cadmium groups received distilled water, whereas the sodium-selenite group received 0.2 mg/kg SSe and the NSe group received 0.2 mg/kg NSe intragastrically for 2 weeks. On the last day, all the other groups were treated with Cd (126 mg/kg) except for the control group. The results obtained in this study showed that NSe alleviated Cd-induced hepatic pathological changes. Furthermore, NSe reduced the activities of ALT and AST as well as the content of MDA, while elevated the activities of T-AOC, T-SOD and GSH ( < 0.05). In addition, the NSe group significantly increased mRNA expressions of Nrf2 pathway related molecules (Nrf2, HO-1, NQO-1, GST, GSH-Px, CAT and SOD) compared to the Cd group ( < 0.05). In conclusion, NSe shows its potentiality to reduce Cd-induced liver injury by inhibiting oxidative stress and activating the Nrf2 pathway.

29Selenium-enriched Bifidobacterium longum protected alcohol and high fat diet induced hepatic injury in mice.PubMed

Hong-Wei Yi, Xiao-Xiao Zhu, Xiao-Li Huang, et al.
Chin J Nat Med. 2020 Mar;18(3):169-177. doi: 10.1016/S1875-5364(20)30018-2.
The objective of this study was to verify the protective effect of Bifidobacterium longum (BL) and the synergistical effect of Selenium and BL on alcohol plus high fat diet (HFD) induced hepatic injury in mice. We also want to explore the mechanism of Selenium-enriched Bifidobacterium longum (SeBL). C57BL/6 mice were treated with alcohol plus HFD with or without different dosage of BL or SeBL for 4 weeks. Serum levels of ALT, AST, TC, TG, LDL-C, HDL-C, FFAs, TNF-α, IL-6 and IL-1β, hepatic MDA level, SOD activity, the mRNA levels of AMPK, PPAR-α and SREBP1 were invested. SeBL inhibited lipid accumulation in hepatocytes; reduced serum AST and ALT levels; improved dyslipidemia; decreased serum FFAs, TC, TG and LDL-C levels. SeBL also inhibited alcohol plus HFD-induced hepatocyte oxidative stress through decrease in hepatic MDA levels and increase in SOD activity. SeBL also regulated lipid metabolism related genes such as AMPK, PPAR-α and SREBP1. Although BL had similar effect as SeBL, SeBL is more effective than BL. SeBL protected mice from alcohol plus HFD-induced hepatic injury in mice because of its inhibitory effect on hepatocellular oxidative stress, lipogenesis and inflammation. Selenium enhanced the protective effect of BL.

30Selenium and liver cirrhosis.PubMed

A Al-Bader, H Abul, T Hussain, et al.
Mol Cell Biochem. 1998 Aug;185(1-2):1-6. doi: 10.1023/a:1006850514295.
Effects of selenium deficiency, induced by thioacetamide, were investigated in rats. Thioacetamide (0.3 g/L) given in drinking water, as expected, caused a significant loss of selenium from the liver. It was accompanied by liver cirrhosis and a significant increase in the liver weight as well as liver to body weight ratio. A significant loss of selenium from spleen was also accompanied by an increase in its weight. Weights of lungs, testis and kidney, however, were not affected by thioacetamide and there was no change in their selenium content. Plasma levels of selenium were significantly reduced in the thioacetamide treated group. All these changes were confirmed to be due to selenium deficiency caused by thioacetamide, as supplementation with selenium reversed these changes. The mode of action of selenium is unknown but may involve anti-oxidant defense mechanisms.

31Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases.PubMed

Chenhui Ma, Li Han, Zheying Zhu, et al.
Biochem Pharmacol. 2022 Nov;205:115242. doi: 10.1016/j.bcp.2022.115242. Epub 2022 Sep 7.
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease worldwide. Minerals including iron, copper, zinc, and selenium, fulfil an essential role in various biochemical processes. Moreover, the identification of ferroptosis and cuproptosis further underscores the importance of intracellular mineral homeostasis. However, perturbation of minerals has been frequently reported in patients with NAFLD and related diseases. Interestingly, studies have attempted to establish an association between mineral disorders and NAFLD pathological features, including oxidative stress, mitochondrial dysfunction, inflammatory response, and fibrogenesis. In this review, we aim to provide an overview of the current understanding of mineral metabolism (i.e., absorption, utilization, and transport) and mineral interactions in the pathogenesis of NAFLD. More importantly, this review highlights potential therapeutic strategies, challenges, future directions for targeting mineral metabolism in the treatment of NAFLD.

32Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment.PubMed

Antonello Pietrangelo
Gastroenterology. 2010 Aug;139(2):393-408, 408.e1-2. doi: 10.1053/j.gastro.2010.06.013. Epub 2010 Jun 11.
In the late 1800s, hemochromatosis was considered an odd autoptic finding. More than a century later, it was finally recognized as a hereditary, multi-organ disorder associated with a polymorphism that is common among white people: a 845G-->A change in HFE that results in C282Y in the gene product. Hemochromatosis is now a well-defined syndrome characterized by normal iron-driven erythropoiesis and the toxic accumulation of iron in parenchymal cells of liver, heart, and endocrine glands. It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood. In mice, deletion of the iron hormone hepcidin and any of 8 genes that regulate its biology, including Hfe, transferrin receptor 2 (Tfr2), and hemojuvelin (Hjv) (which all sense the accumulation of iron that hepcidin corrects) or ferroportin (Fpn) (the cellular iron exporter down-regulated by hepcidin), cause iron overload but not organ disease. In humans, loss of TfR2, HJV, and hepcidin itself or FPN mutations result in full-blown hemochromatosis. Unlike these rare instances, in white people, homozygotes for C282Y polymorphism in HFE are numerous, but they are only predisposed to hemochromatosis; complete organ disease develops in a minority, when these individuals abuse alcohol or from other unidentified modifying factors. HFE gene testing can be used to diagnose hemochromatosis, but analyses of liver histology and clinical features are still required to identify patients with rare, non-HFE forms of the disease. The role of hepcidin in the pathogenesis of hemochromatosis reveals its similarities to endocrine diseases such as diabetes and indicates new approaches to diagnosis and management of this common disorder in iron metabolism.

33Iron overload in non-transfusion-dependent thalassemia: association with genotype and clinical risk factors.PubMed

Adisak Tantiworawit, Pimlak Charoenkwan, Sasinee Hantrakool, et al.
Int J Hematol. 2016 Jun;103(6):643-8. doi: 10.1007/s12185-016-1991-5. Epub 2016 Apr 6.
In the present study, we sought to determine the prevalence of iron overload in patients with non-transfusion-dependent thalassemia (NTDT) and its association with genotype and other clinical risk factors, and to evaluate the correlation between serum ferritin (SF) and liver iron concentration (LIC). Myocardial and liver iron concentration was measured by MRI using a T2* gradient multi-echo sequence in NTDT patients, aged 10-50 years. Of 91 patients, 54 (59 %) had hepatic iron overload. None had cardiac iron overload. The clinical risk factors for hepatic iron overload were age >20 years (adjusted OR 30.2, 95 % CI 4.5-203, p < 0.001), hemoglobin level <7 g/dL (adjusted OR 6.3, 95 % CI 1.01-39.5, p = 0.049), and cumulative RBC transfusion >10 units (adjusted OR 53.6, 95 % CI 3.2-884, p = 0.005). Beta-thalassemia genotype was associated with higher risk of iron overload by univariate analysis, but the association was not significant when adjusted for other clinical factors. The correlation coefficient between SF and LIC was 0.60 (p < 0.001). In conclusion, the prevalence of hepatic iron overload is high in NTDT. Older age, lower hemoglobin level, and higher cumulative RBC transfusion are significant risk factors. SF and LIC show a significant positive correlation.

34Estimation of iron overload with T2*MRI in children treated for hematological malignancies.PubMed

Vinay Munikoty, Kushaljit Singh Sodhi, Anmol Bhatia, et al.
Pediatr Hematol Oncol. 2023 May;40(4):315-325. doi: 10.1080/08880018.2022.2098436. Epub 2022 Jul 14.
Iron overload may contribute to long-term complications in childhood cancer survivors. There are limited reports of assessment of tissue iron overload in childhood leukemia by magnetic resonance imaging (MRI). A cross-sectional, observational study in children treated for hematological malignancy was undertaken. Patients ≥6 months from the end of therapy who had received ≥5 red-cell transfusions were included. Iron overload was estimated by serum ferritin (SF) and T2*MRI. Forty-five survivors were enrolled among 431 treated for hematological malignancies. The median age at diagnosis was 7-years. A median of 8 red-cell units was transfused. The median duration from the end of treatment was 15 months. An elevated SF (>1,000 ng/ml), elevated liver iron concentration (LIC) and myocardial iron concentration (MIC) were observed in 5 (11.1%), 20 (45.4%), and 2 (4.5%) patients, respectively. All survivors with SF >1,000 ng/ml had elevated LIC. The LIC correlated with SF ( < 0.001). MIC lacked correlation with SF or LIC. Factors including the number of red-cell units transfused and duration from the last transfusion were associated with elevated SF ( = 0.001, 0.002) and elevated LIC ( = 0.012, 0.005) in multiple linear regression. SF >595 ng/ml predicted elevated LIC with a sensitivity of 85% and specificity of 91.6% (AUC 91.2%). A cutoff >9 units of red cell transfusions had poor sensitivity and specificity of 70% and 75% (AUC 76.6%) to predict abnormal LIC. SF >600 ng/ml is a robust tool to predict iron overload, and T2*MRI should be considered in childhood cancer survivors with SF exceeding 600 ng/ml.

35Macrophage extracellular traps aggravate iron overload-related liver ischaemia/reperfusion injury.PubMed

Shan Wu, Jing Yang, Guoliang Sun, et al.
Br J Pharmacol. 2021 Sep;178(18):3783-3796. doi: 10.1111/bph.15518. Epub 2021 Jun 13.
BACKGROUND AND PURPOSE: Macrophages regulate iron homeostasis in the liver and play important role in hepatic ischaemia/reperfusion (I/R) injury. This study investigates the role of macrophages in iron overload-related hepatocyte damage during liver I/R. EXPERIMENTAL APPROACH: Liver biopsies from patients undergoing partial hepatectomy with or without hepatic portal occlusion were recruited and markers of hepatocyte cell death and macrophage extracellular traps (METs) were detected. A murine hepatic I/R model was also established in high-iron diet-fed mice. Ferrostatin-1 and deferoxamine were administered to investigate the role of ferroptosis in hepatic I/R injury. The macrophage inhibitor liposome-encapsulated clodronate was used to investigate the interaction between macrophages and ferroptosis. AML12 hepatocytes and RAW264.7 macrophages were co-cultured in vitro. An inhibitor of macrophage extracellular traps was used to evaluate the role and mechanism of these traps and ferroptosis in hepatic I/R injury. KEY RESULTS: Hepatocyte macrophage extracellular trap formation and ferroptosis were greater in patients who underwent hepatectomy with hepatic portal occlusion and in mice subjected to hepatic I/R. Macrophage extracellular traps increased when macrophages were subjected to hypoxia/reoxygenation and when they were co-cultured with hepatocytes. Ferroptosis increased and post-hypoxic hepatocyte survival decreased, which were reversed by inhibition of macrophage extracellular traps. Ferroptosis inhibition attenuated post-ischaemic liver damage. Moreover, iron overload induced hepatic ferroptosis and exacerbated post-ischaemic liver damage, which were reversed by the iron chelator. CONCLUSION AND IMPLICATIONS: Macrophage extracellular traps are in volved in regulating ferroptosis highlighting the therapeutic potential of macrophage extracellular traps and ferroptosis inhibition in reducing liver I/R injury.

36Oral iron supplementation ameliorated alterations in iron uptake and utilization in copper-toxic female Wistar rats.PubMed

Bernard Omokheshi Adele, Ogochuckwu F Eddie-Anunobi, Elsie O Adewoye
JBRA Assist Reprod. 2023 Sep 12;27(3):474-481. doi: 10.5935/1518-0557.20230014.
OBJECTIVE: Women are more susceptible to both iron deficiency and copper toxicity due to monthly flow and estrogen action, respectively. Oral iron is beneficial for menstruating women and enhances erythropoiesis, but both deficiency and excess of copper impact iron absorption and mobilization. The aim of this study was to investigate the possibility of mitigating copper toxicity in female Wistar rats while supplementing with iron. METHODS: 20 female rats (160-180g) were grouped into four: Groups 1 (Control) received 0.3mls normal saline, 2- copper-toxic (100m mg/kg Copper sulphate), 3- Copper-toxic+Iron (100 mg/kg Copper sulphate + 1 mg/kg Ferrous sulphate) and 4- Iron (1 mg/kg Ferrous sulphate). All treatment was administered orally for 5 weeks. Blood was collected retro-orbitally after light anesthesia into EDTA and plain bottles for hematological, serum copper, iron, ferritin and total iron binding capacity (TIBC) analysis. Liver was excised for copper and iron levels while bone marrow was harvested for myeloid/erythroid ratio. The data were analyzed by one-Way ANOVA and statistical significance was considered at p<0.05. RESULTS: Iron supplementation significantly increased packed cell volume, hemoglobin concentration, red blood cell count and myeloid/erythroid ratio, compared to the copper-toxic group. Serum iron and TIBC were significantly increased while liver copper and iron levels reduced significantly in iron supplemented group compared to the copper-toxic group. CONCLUSIONS: Oral iron supplementation mitigated alterations in iron absorption and mobilization following copper toxicity.

37Bodybuilding supplements leading to copper toxicity, encephalopathy, fulminant hepatic failure and rhabdomyolysis.PubMed

John R Richards, Pieter H Scheerlinck, Kelly P Owen, et al.
Am J Emerg Med. 2020 Nov;38(11):2487.e1-2487.e5. doi: 10.1016/j.ajem.2020.05.096. Epub 2020 Jun 2.
Millions of people worldwide use nutritional and dietary supplements, such as vitamins and minerals. These and other performance-enhancing substances are also used by high school, college, and professional athletes, bodybuilders, and amateur sports enthusiasts. The constituents of these supplements and their metabolites may be harmful and not listed on the product label. We present a case report of a 32-year-old bodybuilder using myriad nutritional, performance-enhancing, and weight-loss supplements with life-threatening encephalopathy, hepatic failure, rhabdomyolysis, and copper toxicity mimicking Wilson's disease. Emergency physicians and nurses should be aware of these potential deleterious effects and inquire about supplement use by patients with unexplained multiorgan failure. Family, friends, or acquaintances should be asked to bring the actual products to the hospital for analysis.

38Does dietary copper supplementation enhance or diminish PCB126 toxicity in the rodent liver?PubMed

Ian K Lai, William D Klaren, Miao Li, et al.
Chem Res Toxicol. 2013 May 20;26(5):634-44. doi: 10.1021/tx400049s. Epub 2013 Apr 15.
Copper is essential for the function of the mitochondrial electron transport chain and several antioxidant proteins. However, in its free form copper can participate in Fenton-like reactions that produce reactive hydroxyl radicals. Aryl-hydrocarbon receptor (AhR) agonists, including the most potent polychlorinated biphenyl (PCB) congener, 3,3',4,4',5-pentachlorobiphenyl (PCB126), increase copper levels in rodent livers. This is accompanied by biochemical and toxic changes. To assess the involvement of copper in PCB toxicity, male Sprague-Dawley rats were fed an AIN-93G diet with differing dietary copper levels: low (2 ppm), adequate (6 ppm), and high (10 ppm). After three weeks, rats from each group were given a single ip injection of corn oil (control), 1, or 5 μmol/kg body weight PCB126. Two weeks following injections, biochemical and morphological markers of hepatic toxicity, trace metal status, and hepatic gene expression of metalloproteins were evaluated. Increasing dietary copper was associated with elevated tissue levels of copper and ceruloplasmin. In the livers of PCB126-treated rats, the hallmark signs of AhR activation were present, including increased cytochrome P450 and lipid levels and decreased glutathione. In addition, a doubling of hepatic copper levels was seen, and overall metal homeostasis was disturbed, resulting in decreased hepatic selenium, manganese, zinc, and iron. Expression of key metalloproteins was either decreased (cytochrome c oxidase), unchanged (ceruloplasmin and CuZnSOD), or increased (tyrosinase and metallothioneins 1 and 2) with exposure to PCB126. Increases in metallothionein may contribute/reflect the increased copper seen. Alterations in dietary copper did not amplify or abrogate the hepatic toxicity of PCB126. PCB126 toxicity, i.e., oxidative stress and steatosis, is clearly associated with disturbed metal homeostasis. Understanding the mechanisms of this disturbance may provide tools to prevent liver toxicity by other AhR agonists.

39Influence of cereal bran supplement on cadmium effects in growing rats.PubMed

M G K Callegaro, B G Milbradt, T Diettrich, et al.
Hum Exp Toxicol. 2010 Jun;29(6):467-76. doi: 10.1177/0960327109357777. Epub 2009 Dec 17.
Strategies to diminish cadmium (Cd) absorption are highly desirable especially where Cd exposure due to environmental contamination is still inevitable. Cd toxicity may be influenced by dietary components, such as fiber and minerals. Multimixtures are low-cost cereal bran supplements used in Brazil and in other countries to counteract malnutrition in low-income populations. This study was aimed at evaluating whether multimixture would reduce Cd effects in young rats. Animals received a diet with or without the multimixture plus 0, 5, or 25 mg Cd/kg (control, Cd-5, and Cd-25 groups) during 30 days. The Cd-5 groups were similar to control groups in all parameters analyzed, except in the higher renal Cd concentration. However, the Cd-25 groups had lower biological growth parameters and renal delta-aminolevulinate dehydratase activity, besides higher renal Cd concentration and plasma alanine aminotransferase activity compared to the controls. The multimixture did not prevent Cd effects in the Cd-25 group, but caused a small reduction in renal Cd concentration in the Cd-5 group. Although this multimixture was ineffective to prevent Cd effects at the higher concentration, it seemed to reduce Cd accumulation at the lower Cd dietary concentration, which is similar to levels of human exposure in some polluted areas.

40Selenium restored mitophagic flux to alleviate cadmium-induced hepatotoxicity by inhibiting excessive GPER1-mediated mitophagy activation.PubMed

Honglong Zhang, Jun Yan, Danna Xie, et al.
J Hazard Mater. 2024 Aug 15;475:134855. doi: 10.1016/j.jhazmat.2024.134855. Epub 2024 Jun 13.
Cadmium (Cd) is a common environmental pollutant, while selenium (Se) can ameliorate heavy metal toxicity. Consequently, this study aimed to investigate the protective effects of Se against Cd-induced hepatocyte injury and its underlying mechanisms. To achieve this, we utilized the Dongdagou-Xinglong cohort, BRL3A cell models, and a rat model exposed to Cd and/or Se. The results showed that Se counteracted liver function injury and the decrease in GPER1 levels caused by environmental Cd exposure, and various methods confirmed that Se could protect against Cd-induced hepatotoxicity both in vivo and in vitro. Mechanistically, Cd caused excessive mitophagy activation, evidenced by the colocalization of LC3B, PINK1, Parkin, P62, and TOMM20. Transfection of BRL3A cells with mt-keima adenovirus indicated that Cd inhibited autophagosome-lysosome fusion, thereby impeding mitophagic flux. Importantly, G1, a specific agonist of GPER1, mitigated Cd-induced mitophagy overactivation and hepatocyte toxicity, whereas G15 exacerbates these effects. Notably, Se supplementation attenuated Cd-induced GPER1 protein reduction and excessive mitophagy activation while facilitating autophagosome-lysosome fusion, thereby restoring mitophagic flux. In conclusion, this study proposed a novel mechanism whereby Se alleviated GPER1-mediated mitophagy and promoted autophagosome-lysosome fusion, thus restoring Cd-induced mitophagic flux damage, and preventing hepatocyte injury.

41Remission of copper-induced liver injury through the PXR/NF-kB signaling pathway: The effects of dietary curcumin supplementation in largemouth bass (Micropterus salmoides).PubMed

Hongyan Li, Yiying Fu, Wangbao Gong, et al.
Ecotoxicol Environ Saf. 2024 Oct 15;285:117070. doi: 10.1016/j.ecoenv.2024.117070. Epub 2024 Sep 24.
The pregnane X receptor (PXR)/nuclear factor-kB (NF-kB) signaling pathway plays a critical role in regulating toxin-induced inflammation and apoptosis in mammals. Whether dietary curcumin (CUR) can prevent copper (Cu)-induced liver injury via this signaling pathway remains to be established in aquatic animals. Juvenile largemouth bass (Micropterus salmoides) were exposed to dietary Cu and CUR treatments for 8 weeks. The results showed that chronic Cu exposure induced oxidative stress, causing liver function damage and liver injury. Cu exposure stimulated inflammation by regulating nf-kb and pro-inflammatory genes such as tnfα and il-1β and promoted apoptotic signals in the liver by modulating bcl2 and casp3 mRNA levels. In addition, Pearson correlation analysis verified that inflammatory and apoptotic responses were important indicators of Cu-induced liver injury. CUR attenuated stress responses by enhancing the antioxidant system. Importantly, CUR significantly stimulated PXR mRNA and protein levels in the Cu + CUR group and suppressed NF-κB activation to inhibit the inflammatory and apoptotic signaling cascade. These results suggest that CUR may be an effective activator of PXR in teleost fishes, exerting cytoprotective effects on Cu-induced liver injury via a PXR-mediated NF-κB repression mechanism. In conclusion, this study is the first to demonstrate that CUR may act as a potent PXR ligand that exerts hepatoprotective effects against Cu-induced liver injury. The findings shed light on the specific regulatory role of the PXR/NF-κB signaling pathway in liver pathogenesis and its potential as a therapeutic target in teleost fishes.

42Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications.PubMed

Jiezhong Chen, Luis Vitetta
Int J Mol Sci. 2020 Jul 23;21(15):5214. doi: 10.3390/ijms21155214.
Gut microbiota dysregulation plays a key role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through its metabolites. Therefore, the restoration of the gut microbiota and supplementation with commensal bacterial metabolites can be of therapeutic benefit against the disease. In this review, we summarize the roles of various bacterial metabolites in the pathogenesis of NAFLD and their therapeutic implications. The gut microbiota dysregulation is a feature of NAFLD, and the signatures of gut microbiota are associated with the severity of the disease through altered bacterial metabolites. Disturbance of bile acid metabolism leads to underactivation of bile acid receptors FXR and TGR5, causal for decreased energy expenditure, increased lipogenesis, increased bile acid synthesis and increased macrophage activity. Decreased production of butyrate results in increased intestinal inflammation, increased gut permeability, endotoxemia and systemic inflammation. Dysregulation of amino acids and choline also contributes to lipid accumulation and to a chronic inflammatory status. In some NAFLD patients, overproduction of ethanol produced by bacteria is responsible for hepatic inflammation. Many approaches including probiotics, prebiotics, synbiotics, faecal microbiome transplantation and a fasting-mimicking diet have been applied to restore the gut microbiota for the improvement of NAFLD.

43Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications.PubMed

Jie Fang, Chen-Huan Yu, Xue-Jian Li, et al.
Front Cell Infect Microbiol. 2022 Nov 8;12:997018. doi: 10.3389/fcimb.2022.997018. eCollection 2022.
The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing recently and has become one of the most common clinical liver diseases. Since the pathogenesis of NAFLD has not been completely elucidated, few effective therapeutic drugs are available. As the "second genome" of human body, gut microbiota plays an important role in the digestion, absorption and metabolism of food and drugs. Gut microbiota can act as an important driver to advance the occurrence and development of NAFLD, and to accelerate its progression to cirrhosis and hepatocellular carcinoma. Growing evidence has demonstrated that gut microbiota and its metabolites directly affect intestinal morphology and immune response, resulting in the abnormal activation of inflammation and intestinal endotoxemia; gut dysbiosis also causes dysfunction of gut-liver axis alteration of bile acid metabolism pathway. Because of its composition diversity and disease-specific expression characteristics, gut microbiota holds strong promise as novel biomarkers and therapeutic targets for NAFLD. Intervening intestinal microbiota, such as antibiotic/probiotic treatment and fecal transplantation, has been a novel strategy for preventing and treating NAFLD. In this article, we have reviewed the emerging functions and association of gut bacterial components in different stages of NAFLD progression and discussed its potential implications in NAFLD diagnosis and therapy.

44Role of Probiotics in Non-alcoholic Fatty Liver Disease: Does Gut Microbiota Matter?PubMed

Chencheng Xie, Dina Halegoua-DeMarzio
Nutrients. 2019 Nov 19;11(11):2837. doi: 10.3390/nu11112837.
Non-alcoholic fatty liver disease (NAFLD) is the hepatic consequence of metabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. The connection between gut microbiota (GM) and NAFLD has attracted significant attention in recent years. Data has shown that GM affects hepatic lipid metabolism and influences the balance between pro/anti-inflammatory effectors in the liver. Although studies reveal the association between GM dysbiosis and NAFLD, decoding the mechanisms of gut dysbiosis resulting in NAFLD remains challenging. The potential pathophysiology that links GM dysbiosis to NAFLD can be summarized as: (1) disrupting the balance between energy harvest and expenditure, (2) promoting hepatic inflammation (impairing intestinal integrity, facilitating endotoxemia, and initiating inflammatory cascades with cytokines releasing), and (3) altered biochemistry metabolism and GM-related metabolites (i.e., bile acid, short-chain fatty acids, aromatic amino acid derivatives, branched-chain amino acids, choline, ethanol). Due to the hypothesis that probiotics/synbiotics could normalize GM and reverse dysbiosis, there have been efforts to investigate the therapeutic effect of probiotics/synbiotics in patients with NAFLD. Recent randomized clinical trials suggest that probiotics/synbiotics could improve transaminases, hepatic steatosis, and reduce hepatic inflammation. Despite these promising results, future studies are necessary to understand the full role GM plays in NAFLD development and progression. Additionally, further data is needed to unravel probiotics/synbiotics efficacy, safety, and sustainability as a novel pharmacologic approaches to NAFLD.

45The Role of Gut-Derived Lipopolysaccharides and the Intestinal Barrier in Fatty Liver Diseases.PubMed

Lingxuan An, Ulrich Wirth, Dominik Koch, et al.
J Gastrointest Surg. 2022 Mar;26(3):671-683. doi: 10.1007/s11605-021-05188-7. Epub 2021 Nov 3.
BACKGROUND: Hepatosteatosis is the earliest stage in the pathogenesis of nonalcoholic fatty (NAFLD) and alcoholic liver disease (ALD). As NAFLD is affecting 10-24% of the general population and approximately 70% of obese patients, it carries a large economic burden and is becoming a major reason for liver transplantation worldwide. ALD is a major cause of morbidity and mortality causing 50% of liver cirrhosis and 10% of liver cancer related death. Increasing evidence has accumulated that gut-derived factors play a crucial role in the development and progression of chronic liver diseases. METHODS: A selective literature search was conducted in Medline and PubMed, using the terms "nonalcoholic fatty liver disease," "alcoholic liver disease," "lipopolysaccharide," "gut barrier," and "microbiome." RESULTS: Gut dysbiosis and gut barrier dysfunction both contribute to chronic liver disease by abnormal regulation of the gut-liver axis. Thereby, gut-derived lipopolysaccharides (LPS) are a key factor in inducing the inflammatory response of liver tissue. The review further underlines that endotoxemia is observed in both NAFLD and ALD patients. LPS plays an important role in conducting liver damage through the LPS-TLR4 signaling pathway. Treatments targeting the gut microbiome and the gut barrier such as fecal microbiota transplantation (FMT), probiotics, prebiotics, synbiotics, and intestinal alkaline phosphatase (IAP) represent potential treatment modalities for NAFLD and ALD. CONCLUSIONS: The gut-liver axis plays an important role in the development of liver disease. Treatments targeting the gut microbiome and the gut barrier have shown beneficial effects in attenuating liver inflammation and need to be further investigated.

46Akkermansia muciniphila Ameliorates Acetaminophen-Induced Liver Injury by Regulating Gut Microbial Composition and Metabolism.PubMed

Jiafeng Xia, Longxian Lv, Boqiang Liu, et al.
Microbiol Spectr. 2022 Feb 23;10(1):e0159621. doi: 10.1128/spectrum.01596-21. Epub 2022 Feb 2.
The gut microbiota drives individual sensitivity to excess acetaminophen (APAP)-mediated hepatotoxicity. It has been reported that the bacterium Akkermansia muciniphila protects hosts against liver disease via the liver-gut axis, but its therapeutic potential for drug-induced liver injury remains unclear. In this study, we aimed to investigate the effect of A. muciniphila on APAP-induced liver injury and the underlying mechanism. Administration of A. muciniphila efficiently alleviated APAP-induced hepatotoxicity and reduced the levels of serum alanine aminotransferase (ALT) and aspartate transaminase (AST). A. muciniphila significantly attenuated APAP-induced oxidative stress and the inflammatory response, as evidenced by restoration of the reduced glutathione/oxidized glutathione (GSH/GSSG) balance, enhanced superoxide dismutase (SOD) activity, reduced proinflammatory cytokine production, and alleviation of macrophage and neutrophil infiltration. Moreover, A. muciniphila maintained gut barrier function, reshaped the perturbed microbial community and promoted short-chain fatty acid (SCFA) secretion. The beneficial effects of A. muciniphila were accompanied by alterations in hepatic gene expression at the transcriptional level and activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results suggested that A. muciniphila could be a potential pretreatment for APAP-induced liver injury. Our work revealed that A. muciniphila attenuated APAP-induced liver injury by alleviating oxidative stress and inflammation in the liver, and its hepatoprotective effect was accompanied by activation of the PI3K/Akt pathway and mediated by regulation of the composition and metabolic function of the intestinal microbiota. This finding suggested that the microbial community is a non-negligible impact on drug metabolism and probiotic administration could be a potential therapy for drug-induced liver injury.

47Drug-induced liver injury.PubMed

Dev Katarey, Sumita Verma
Clin Med (Lond). 2016 Dec;16(Suppl 6):s104-s109. doi: 10.7861/clinmedicine.16-6-s104.
Drug-induced liver injury (DILI) remains the most common cause of acute liver failure (ALF) in the western world. Excluding paracetamol overdose, nearly all DILI encountered in the clinical setting is idiosyncratic in nature because affected individuals represent only a small proportion of those treated with such drugs. In many cases, the mechanism for idiosyncrasy is immune-mediation and is often identified by genetic risk determined by human leukocyte antigen variants. In the absence of diagnostic tests and/or biomarkers, the diagnosis of DILI requires a high index of suspicion after diligently excluding other causes of abnormal liver tests. Antibiotics are the class of drugs most frequently associated with idiosyncratic DILI, although recent studies indicate that herbal and dietary supplements are an increasingly recognised cause. It is imperative that upon development of DILI the culprit drug be discontinued, especially in the presence of elevated transaminases (aspartate aminotransferase/alanine aminotransferase ratio ≥5 times the upper limit of normal) and/or jaundice. Risk factors for the development ALF include hepatocellular DILI and female gender, the treatment being supportive with some benefit of N-acetylcysteine in the early stages. In view of the poor transplant-free survival in idiosyncratic DILI, early consideration for liver transplant is mandatory.

48Drug-Induced Liver Injury.PubMed

Leslie A Hamilton, Angela Collins-Yoder, Rachel E Collins
AACN Adv Crit Care. 2016 Oct;27(4):430-440. doi: 10.4037/aacnacc2016953.
Drug-induced liver injury (DILI) can result from both idiosyncratic and intrinsic mechanisms. This article discusses the clinical impact of DILI from a broad range of medications as well as herbal and dietary supplements. Risk factors for idiosyncratic DILI (IDILI) are the result of multiple host, environmental, and compound factors. Some triggers of IDILI often seen in critical care include antibiotics, antiepileptic medications, statins, novel anticoagulants, proton pump inhibitors, inhaled anesthetics, nonsteroidal anti-inflammatory agents, methotrexate, sulfasalazine, and azathioprine. The mechanism of IDILI due to these medications varies, and the resulting damage can be cholestatic, hepatocellular, or mixed. The primary treatment of IDILI is to discontinue the causative agent. DILI due to acetaminophen is intrinsic because the liver damage is predictably aligned with the dose ingested. Acute acetaminophen ingestion can be treated with activated charcoal or N-acetylcysteine. Future areas of research include identification of mitochondrial stress biomarkers and of the patients at highest risk for DILI.

49Toxicity of green tea extracts and their constituents in rat hepatocytes in primary culture.PubMed

M Schmidt, H-J Schmitz, A Baumgart, et al.
Food Chem Toxicol. 2005 Feb;43(2):307-14. doi: 10.1016/j.fct.2004.11.001.
Recent reports on sporadic cases of liver disorders (acute hepatitis, icterus, hepatocellular necrosis) after ingestion of dietary supplements based on hydro-alcoholic extracts from green tea leaves led to restrictions of the marketing of such products in certain countries of the EU. Since green tea is considered to exert a number of beneficial health effects, and, therefore, green tea products are widely used as dietary supplements, we were interested in the possible mechanism of hepatotoxicity of green tea extracts and in the components involved in such effects. Seven hours after seeding on collagen, rat hepatocytes in primary culture were treated with various hydro-alcoholic green tea extracts (two different native 80% ethanolic dry extracts and an 80% ethanolic dry extract cleared from lipophilic compounds). Cells were washed, and reduction of resazurin, used as a viability parameter monitoring intact mitochondrial function, was determined. It was found that all seven green tea extracts examined enhanced resazurin reduction significantly at a concentration range of 100-500 microg/ml medium, while a significant decrease was observed at 1-3mg/ml medium. Decreased levels were concomitant with abundant necrosis as observed by microscopic inspection of the cultures and with increased leakage of lactate dehydrogenase activity from the cells. In a separate series of experiments, the green tea constituents (-)-epicatechin, (-)-epigallocatechin-3-gallate, caffeine and theanine were tested at concentrations reflecting their levels in a typical green tea extract. Synthetic (+)-epigallocatechin (200 microM) was used for comparison. Cytotoxicity was found with (-)-epigallocatechin-3-gallate only. The concomitant addition of 0.25 mM ascorbate/0.05 mM alpha-tocopherol had no influence on cytotoxicity. In conclusion, our results suggest that high concentrations of green tea extract can exert acute toxicity in rat liver cells. (-)-Epigallocatechin-3-gallate seems to be a key constituent responsible for this effect. The relatively low bioavailability of catechins reported after oral exposure to green tea argues, however, against a causal role of these constituents in the reported liver disorders.

50Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins.PubMed

Giuseppe Galati, Alison Lin, Amira M Sultan, et al.
Free Radic Biol Med. 2006 Feb 15;40(4):570-80. doi: 10.1016/j.freeradbiomed.2005.09.014. Epub 2005 Nov 9.
Tea phenolic acids and catechins containing gallic acid moieties are most abundant in green tea, and various medical benefits have been proposed from their consumption. In the following, the cytotoxicities of these major tea phenolics toward isolated rat hepatocytes have been ranked and the mechanisms of cytotoxicity evaluated. The order of cytotoxic effectiveness found was epigallocatechin-3-gallate>propyl gallate>epicatechin-3-gallate>gallic acid, epigallocatechin>epicatechin. Using gallic acid as a model tea phenolic and comparing it with the tea catechins and gallic acid-derivative food supplements, the major cytotoxic mechanism found with hepatocytes was mitochondrial membrane potential collapse and ROS formation. Epigallocatechin-3-gallate was also the most effective at collapsing the mitochondrial membrane potential and inducing ROS formation. Liver injury was also observed in vivo when these tea phenolics were administered ip to mice, as plasma alanine aminotransferase levels were significantly increased. In contrast, GSH conjugation, methylation, metabolism by NAD(P)H:quinone oxidoreductase 1, and formation of an iron complex were important in detoxifying the gallic acid. In addition, for the first time, the GSH conjugates of gallic acid and epigallocatechin-3-gallate have been identified using mass spectrometry. These results add insight into the cytotoxic and cytoprotective mechanisms of the simple tea phenolic acids and the more complex tea catechins.

51Dose-dependent functionality and toxicity of green tea polyphenols in experimental rodents.PubMed

Akira Murakami
Arch Biochem Biophys. 2014 Sep 1;557:3-10. doi: 10.1016/j.abb.2014.04.018. Epub 2014 May 9.
A large number of physiologically functional foods are comprised of plant polyphenols. Their antioxidative activities have been intensively studied for a long period and proposed to be one of the major mechanisms of action accounting for their health promotional and disease preventive effects. Green tea polyphenols (GTPs) are considered to possess marked anti-oxidative properties and versatile beneficial functions, including anti-inflammation and cancer prevention. On the other hand, some investigators, including us, have uncovered their toxicity at high doses presumably due to pro-oxidative properties. For instance, both experimental animal studies and epidemiological surveys have demonstrated that GTPs may cause hepatotoxicity. We also recently showed that diets containing high doses (0.5-1%) of a GTP deteriorated dextran sodium sulfate (DSS)-induced intestinal inflammation and carcinogenesis. In addition, colitis mode mice fed a 1% GTP exhibited symptoms of nephrotoxicity, as indicated by marked elevation of serum creatinine level. This diet also increased thiobarbituric acid-reactive substances, a reliable marker of oxidative damage, in both kidneys and livers even in normal mice, while the expression levels of antioxidant enzymes and heat shock proteins (HSPs) were diminished in colitis and normal mice. Intriguingly, GTPs at 0.01% and 0.1% showed hepato-protective activities, i.e., they significantly suppressed DSS-increased serum aspartate aminotransferase and alanine aminotransferase levels. Moreover, those diets remarkably restored DSS-down-regulated expressions of heme oxygenase-1 and HSP70 in livers and kidneys. Taken together, while low and medium doses of GTPs are beneficial in colitis model mice, unwanted side-effects occasionally emerge with high doses. This dose-dependent functionality and toxicity of GTPs are in accordance with the concept of hormesis, in which mild, but not severe, stress activates defense systems for adaptation and survival.

52Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study.PubMed

Qin Dong, Na Li, Qi Li, et al.
Front Pharmacol. 2015 Oct 2;6:217. doi: 10.3389/fphar.2015.00217. eCollection 2015.
Heshouwu (HSW), the dry roots of Polygonum multiflorum, a classical traditional Chinese medicine is used as a tonic for a wide range of conditions, particularly those associated with aging. However, it tends to be taken overdose or long term in these years, which has resulted in liver damage reported in many countries. In this study, the indicative roles of nine bile acids (BAs) were evaluated to offer potential biomarkers for HSW induced liver injury. Nine BAs including cholic acid (CA) and chenodeoxycholic acid (CDCA), taurocholic acid (TCA), glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), deoxycholic acid (DCA), glycodeoxycholic acid (GDCA), ursodeoxycholic acid (UDCA), and hyodeoxycholic acid (HDCA) in rat bile and serum were detected by a developed LC-MS method after 42 days treatment. Partial least square-discriminate analysis (PLS-DA) was applied to evaluate the indicative roles of the nine BAs, and metabolism of the nine BAs was summarized. Significant change was observed for the concentrations of nine BAs in treatment groups compared with normal control; In the PLS-DA plots of nine BAs in bile, normal control and raw HSW groups were separately clustered and could be clearly distinguished, GDCA was selected as the distinguished components for raw HSW overdose treatment group. In the PLS-DA plots of nine BAs in serum, the normal control and raw HSW overdose treatment group were separately clustered and could be clearly distinguished, and HDCA was selected as the distinguished components for raw HSW overdose treatment group. The results indicated the perturbation of nine BAs was associated with HSW induced liver injury; GDCA in bile, as well as HDCA in serum could be selected as potential biomarkers for HSW induced liver injury; it also laid the foundation for the further search on the mechanisms of liver injury induced by HSW.

53Identification of intrinsic hepatotoxic compounds in Polygonum multiflorum Thunb. using machine-learning methods.PubMed

Xiaowen Hu, Tingting Du, Shengyun Dai, et al.
J Ethnopharmacol. 2022 Nov 15;298:115620. doi: 10.1016/j.jep.2022.115620. Epub 2022 Aug 10.
ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb. (PM) is a herb, extracts of which have been used as Chinese medicine for years. Although it is believed to be beneficial to the liver, heart, and kidneys, it causes idiosyncratic drug-induced liver injury (DILI). AIM OF THE STUDY: We propose that the intrinsic DILI caused by natural products in PM (NPPM) is an important complementary mechanism to PM-related herb-induced liver injury, and aim to identify the ingredients with high DILI potential by machine learning methods. MATERIALS AND METHODS: One hundred and ninety-seven NPPM were collected from the literature to identify the intrinsic hepatotoxic compounds. Additionally, a DILI-labeled dataset consisting of 2384 compounds was collected and randomly split into training and test sets. A diparametric optimization method was developed to tune the parameters of extended-connectivity fingerprints (ECFPs), Rdkit, and atom-pair fingerprints as well as those of machine-learning (ML) algorithms. Subsequently, K means were employed to cluster the NPPM that were predicted to have a high DILI risk. An in vitro cell-viability assay was performed using HepaRG cells to validate the prediction results. RESULTS: ECFPs with the top 35% of features ranked by the F-value with support vector machine (SVM) yielded the best performance. The optimized SVM model achieved an accuracy of 0.761 and recall value of 0.834 on the test dataset. The silico screening for NPPM resulted in 47 ingredients with high DILI potential, which were clustered into six groups based on the elbow method. A representative subgroup that contained 21 ingredients, of which two dianthrones exhibited the lowest IC value (0.7-0.9 μM) and anthraquinones showed moderate toxicity (15-25 μM), was constructed. CONCLUSION: Using ML methods and in vitro screening, two classes of compounds, dianthrones and anthraquinones, were predicted and validated to have a high risk of DILI. The diparametric optimization method used in this study could provide a useful and powerful tool to screen toxicants for large datasets and is available at https://github.com/dreadlesss/Hepatotoxicity_predictor.

54-Induced Liver Injury: Clinical Characteristics, Risk Factors, Material Basis, Action Mechanism and Current Challenges.PubMed

Yi Liu, Wenping Wang, Mingyi Sun, et al.
Front Pharmacol. 2019 Dec 13;10:1467. doi: 10.3389/fphar.2019.01467. eCollection 2019.
Thunb. (PM), called in China, is a popular Chinese medicine in clinical practice. Several clinical studies have been conducted to evaluate the traditional therapeutic claims and to study the potential therapeutic activity of PM in dyslipidemia and neurodegenerative diseases, highlighting available clinical evidence. In recent years, reports on clinical adverse reactions of Raw Radix (RPM) and Praeparata (PMP) have been on the increase, especially with respect to liver injury. Most liver injury cases had been assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) in this paper. However, the components of PM responsible for the reported hepatotoxic effects have not yet been identified. Moreover, many of the reports are contradictory, while studies on the mechanism involved in PM-induced liver damage are not comprehensive. This study was aimed at reviewing the status of research on liver injury due to PM, including clinical characteristics, risk factors, material basis research and mechanism of action, with a view to understanding PM-induced hepatotoxicity, and taking reasonable and effective measures to prevent it. In short, quality control is still one of the major safety problems in TCM drug safety concerns. The model of safety monitoring and risk management of PM drugs is not yet developed. Indeed, the characteristics and risk factors associated with PM require both proper understanding and control of the risk by strengthening standardization of clinical applications, basic science research, quality control in manufacturing, active monitoring methodology and enhancement of international communication and cooperation. Measures should also be encouraged and implemented to promote healthy development of the TCM industry.

55Polygonum multiflorum: Recent updates on newly isolated compounds, potential hepatotoxic compounds and their mechanisms.PubMed

Tekleab Teka, Liming Wang, Jian Gao, et al.
J Ethnopharmacol. 2021 May 10;271:113864. doi: 10.1016/j.jep.2021.113864. Epub 2021 Jan 21.
ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb.(PM), (known as Heshouwu () in China) is one of the most important and well mentioned Chinese medicinal herbs in the literature for its use in blackening hair, nourishing liver and kidney, anti-aging, anti-hyperlipidemia, antioxidant, anti-inflammatory, anticancer, hepatoprotection, cardio-protection and improving age-related cognitive dysfunction. The purpose of this review is to give a comprehensive and recent update on PM: new compounds or isolated for the first time, potential hepatotoxic compounds and their mechanisms. Moreover, future perspectives and challenges in the future study of this plant are conversed which will make a new base for further study on PM. MATERIALS AND METHODS: A comprehensive review of relevant published literature on PM using the scientific databases SCOPUS, PubMed, and Science Direct was done. RESULTS: PM is broadly produced in many provinces of China and well known in other Eastern Asian Countries for its ethno-medical uses. Previous phytochemical investigation of PM had led to the isolation of more than 175 compounds including recently isolated 70 new compounds. Most of the new compounds isolated after 2015 are majorly dianthrone glycosides and stilbene glycosides. Processing has also a significant effect on chemical composition, pharmacological activities, and toxicity of PM. PM-induced liver injury is increasing after the first report in Hong Kong in 1996. Hepatotoxicity of PM was constantly reported in Japan, Korea, China, Australia, Britain, Italy, and other countries although its toxicity is related to idiosyncratic hepatotoxicity. More interestingly, although there is indispensable interest to predict idiosyncratic hepatotoxicity of PM and understand its mechanisms, the responsible hepatotoxic compounds and mechanisms of liver damage induced by PM are still not clear. There is a big controversy on the identification of the most responsible constituent. Anthraquinone and stilbene compounds in PM, mainly emodine and TSG are mentioned in the literature to be the main responsible hepatotoxic compounds. However, comparing the two compounds, which one is the more critical toxic agent for PM-induced hepatotoxicity is not well answered. Affecting different physiological and metabolic pathways such as oxidative phosphorylation and TCA cycle pathway, metabolic pathways, bile acid excretion pathway and genetic polymorphisms are among the mechanisms of hepatotoxicity of PM. CONCLUSION: Deeper and effective high throughput experimental studies are still research hotspots to know the most responsible constituent and the mechanism of PM-induced hepatotoxicity.

56Research progress on hepatotoxicity mechanism of polygonum multiflorum and its main components.PubMed

Liping Gong, Xianhui Shen, Nana Huang, et al.
Toxicon. 2024 Sep;248:108040. doi: 10.1016/j.toxicon.2024.108040. Epub 2024 Jul 20.
As a traditional tonic Chinese medicine, Polygonum multiflorum is widely used in clinical practice. However, with the deepening of modern pharmacological research, its drug toxicity, especially hepatotoxicity, has become increasingly prominent. Based on a large number of clinical and experimental evidence, it has been confirmed that Polygonum multiflorum and its main active ingredients such as anthraquinones and diphenylethylene glucoside can cause different degrees of hepatotoxicity. Further studies have shown that the toxicological mechanisms involved in the hepatotoxicity of different extracts and components of Polygonum multiflorum may include oxidative phosphorylation, bile acid excretion, different metabolic pathways, genetic and metabolic factors, immune homeostasis, etc. By sorting out and summarizing the literature related to hepatotoxicity of Polygonum multiflorum in recent years, this paper discussed the hepatotoxicity mechanism of Polygonum multiflorum and its main components and some contradictions in related reports.

57Mitochondrial stress response in drug-induced liver injury.PubMed

Jing Zheng, Qiulin Yuan, Cao Zhou, et al.
Mol Biol Rep. 2021 Oct;48(10):6949-6958. doi: 10.1007/s11033-021-06674-6. Epub 2021 Aug 25.
Drug-induced liver injury (DILI) caused by the ingestion of medications, herbs, chemicals or dietary supplements, is a clinically widespread health problem. The underlying mechanism of DILI is the formation of reactive metabolites, which trigger mitochondrial oxidative stress and the opening of mitochondrial permeability transition (MPT) pores through direct toxicity or immune response, leading to cell inflammation, apoptosis, and necrosis. Traditionally, mitochondria play an indispensable role in maintaining the physiological and biochemical functions of cells by producing ATP and mediating intracellular signal transduction; drugs can typically stimulate the mitochondria and, in the case of sustained stress, can eventually cause impairment of mitochondrial function and metabolic activity. Meanwhile, the mitochondrial stress response, as an adaptive protective mechanism, occurs when mitochondrial homeostasis is threatened. In this review, we summarize the relevant frontier researches of the protective effects of mitochondrial stress response in DILI as well as the potential related mechanisms, thus providing some thoughts for the clinical treatment of DILI.

58Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence.PubMed

Nouf Aljobaily, Michael J Viereckl, David S Hydock, et al.
Nutrients. 2020 Dec 24;13(1):41. doi: 10.3390/nu13010041.
: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.

59Curcumin supplementation alleviates hepatic fat content associated with modulation of gut microbiota-dependent bile acid metabolism in patients with nonalcoholic simple fatty liver disease: a randomized controlled trial.PubMed

Youming He, Xiaobing Chen, Yongchun Li, et al.
Am J Clin Nutr. 2024 Jul;120(1):66-79. doi: 10.1016/j.ajcnut.2024.05.017. Epub 2024 May 23.
BACKGROUND: Our previous studies showed that curcumin prevented hepatic steatosis in animal models. OBJECTIVES: This study aimed to assess the effects of curcumin on hepatic fat content, body composition, and gut microbiota-dependent bile acid (BA) metabolism in patients with nonalcoholic simple fatty liver (NASFL). METHODS: In a 24-wk double-blind randomized trial, 80 patients with NASFL received 500 mg/d curcumin or placebo. Hepatic fat content was measured using FibroTouch-based controlled attenuation parameters (CAPs). Microbial composition and BA metabolites were analyzed using 16S rRNA sequencing and metabolomics. RESULTS: Curcumin consumption significantly reduced CAP value compared with placebo (-17.5 dB/m; 95% confidence interval [CI]: -27.1, -7.8 dB/m; P < 0.001). This corresponded to reduction in weight (-2.6 kg; 95% CI: -4.4, -0.8 kg; P < 0.001) and BMI (-1.0 kg/m; 95% CI: -2.0, -0.1 kg/m; P = 0.032) compared with placebo group. Additionally, free fatty acid (-0.12 mmol/L; 95% CI: -0.20, -0.04 mmol/L; P = 0.004), triglycerides (-0.29 mmol/L; 95% CI: -0.41, -0.14 mmol/L; P < 0.001), fasting blood glucose (-0.06 mmol/L; 95% CI: -0.12, -0.01 mmol/L; P = 0.038), hemoglobin A1c (-0.06%; 95% CI: -0.33, -0.01%; P = 0.019), and insulin (-4.94 μU/L; 95% CI: -9.73, -0.15 μU/L; P = 0.043) showed significant reductions in the curcumin group compared with placebo group. Gut microbiota analysis indicated that curcumin significantly decreased Firmicutes to Bacteroidetes ratio and significantly increased Bacteroides abundance. Serum levels of deoxycholic acid, the most potent activator of Takeda G protein-coupled receptor 5 (TGR5), were significantly elevated after curcumin intervention (37.5 ng/mL; 95% CI: 6.7, 68.4 ng/mL; P = 0.018). Curcumin treatment also increased TGR5 expression in peripheral blood mononuclear cells and serum glucagon-like peptide-1 levels (0.73 ng/mL; 95% CI: 0.16, 1.30 ng/mL; P = 0.012). CONCLUSIONS: Improvements in gut microbiota-dependent BA metabolism and TGR5 activation after 24-wk curcumin intervention were associated with a reduction in hepatic fat content in patients with NASFL, providing evidence that curcumin is a potential nutritional therapy for NASFL. The trial was registered at www.chictr.org.cn as ChiCTR2200058052.

60Lactobacillus helveticus attenuates alcoholic liver injury via regulation of gut microecology in mice.PubMed

Jiawen Lv, Guanjing Lang, Qiangqiang Wang, et al.
Microb Biotechnol. 2024 Oct;17(10):e70016. doi: 10.1111/1751-7915.70016.
Previous reports have demonstrated that alcohol consumption significantly reduces the abundance of Lactobacillus in the gut. In this study, we selected five species of the genus Lactobacillus, commonly found in fermented foods, and acknowledged them as safe, edible, and effective in preventing or treating certain diseases, to evaluate their effects on alcoholic liver disease (ALD). By comparing the liver damage indices in each group, we found that the type strain of Lactobacillus helveticus (LH, ATCC 15009) had the most marked alleviating effect on ALD-induced liver injury. Furthermore, experiments combining microbiomics and metabolomics were conducted to explore the mechanisms underlying the hepatoprotective effects of LH. Finally, we discovered that LH mitigated ethanol-induced liver steatosis and inflammation in ALD mice by altering the structure and function of the gut microbiome, increasing intestinal levels of short-chain fatty acids (SCFAs), and enhancing gut barrier integrity. These findings suggest a potential strategy for the clinical management of patients with ALD.

61Silymarin decreases liver stiffness associated with gut microbiota in patients with metabolic dysfunction-associated steatotic liver disease: a randomized, double-blind, placebo-controlled trial.PubMed

Yufeng Jin, Xin Wang, Ke Chen, et al.
Lipids Health Dis. 2024 Aug 3;23(1):239. doi: 10.1186/s12944-024-02220-y.
BACKGROUND: Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated steatotic liver disease (MASLD) are limited and inconclusive, particularly when it is administered alone. The low bioavailability of silymarin highlights the possible influence of gut microbiota on the effectiveness of silymarin; however, no human studies have investigated this aspect. OBJECTIVE: To determine the potential efficacy of silymarin in improving MASLD indicators and to investigate the underlying mechanisms related to gut microbiota. METHOD: In this 24-week randomized, double-blind, placebo-controlled trial, 83 patients with MASLD were randomized to either placebo (n = 41) or silymarin (103.2 mg/d, n = 42). At 0, 12, and 24 weeks, liver stiffness and hepatic steatosis were assessed using FibroScan, and blood samples were gathered for biochemical detection, while faecal samples were collected at 0 and 24 weeks for 16S rRNA sequencing. RESULTS: Silymarin supplementation significantly reduced liver stiffness (LSM, -0.21 ± 0.17 vs. 0.41 ± 0.17, P = 0.015) and serum levels of γ-glutamyl transpeptidase (GGT, -8.21 ± 3.01 vs. 1.23 ± 3.16, P = 0.042) and ApoB (-0.02 ± 0.03 vs. 0.07 ± 0.03, P = 0.023) but had no significant effect on the controlled attenuation parameter (CAP), other biochemical indicators (aminotransferases, total bilirubin, glucose and lipid parameters, hsCRP, SOD, and UA), physical measurements (DBP, SBP, BMI, WHR, BF%, and BMR), or APRI and FIB-4 indices. Gut microbiota analysis revealed increased species diversity and enrichment of Oscillospiraceae in the silymarin group. CONCLUSION: These findings suggest that silymarin supplementation could improve liver stiffness in MASLD patients, possibly by modulating the gut microbiota. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200059043).

62Safety evaluation of Bon-santé cleanser® polyherbal in male Wistar rats.PubMed

O E Kale, O Awodele
BMC Complement Altern Med. 2016 Jul 7;16:188. doi: 10.1186/s12906-016-1188-8.
BACKGROUND: The potential harm of medicinal herbs has been recently observed following herbal toxicity studies after ingestion of polyherbal remedies. This was the rationale for the food and drug regulatory agency decision for thorough safety evaluation of herbal medicines. Androgenic, antipyretic, analgesic and anti-inflammatory potentials as well as chemical compositions of extracts of massularia acuminata, terminalia ivorensis, anogeissus leiocarpus and macuna pruriens respectively have been documented. Thus, Bon-santé cleanser® (BSC) is formulated from these medicinal plants with the intention to boost body hormones and energizes the body. Considering the wide usage of BSC, we investigated on its safety in male Wistar rats. METHODS: Thirty-two male Wistar rats weighing 201.9 ± 7.5 g were grouped into four treatment groups of eight per group. Group I, (control) received distilled water (10 ml/kg). Groups II-IV received 250 mg/kg, 500 mg/kg and 1000 mg/kg of BSC per oral respectively. Each group was treated for sixty days. RESULTS: Acute toxicity test, in male Wistar albino mice, showed that LD50 was 600 mg/kg via i.p. while 4 g/kg was nonlethal after oral administration in mice. Hepatic and renal biomarker enzymes were unaltered in all rats. Increased in PCV (p <0.05) was observed at 500 mg/kg. BSC modulates antioxidants biomarkers following sub-chronic administration and increased serum Na(+) (p >0.05). BSC at 1000 mg/kg caused mild inflammation of the liver and heart but not kidneys histologically. CONCLUSIONS: BSC has been found to be relatively safe in Wistar rats. Although, our findings indicate that herbal therapy with BSC should be done with caution as a mild alteration in the liver and heart architectures were observed.

63Vitamin D and Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD): An Update.PubMed

Ilaria Barchetta, Flavia Agata Cimini, Maria Gisella Cavallo
Nutrients. 2020 Oct 28;12(11):3302. doi: 10.3390/nu12113302.
Non-alcoholic fatty liver disease (NAFLD) is the first cause of chronic liver disease worldwide; it ranges from simple steatosis to steatohepatitis (NASH) and, potentially, cirrhosis and hepatocarcinoma. NAFLD is also an independent risk factor for type 2 diabetes, cardiovascular diseases, and mortality. As it is largely associated with insulin resistance and related disorders, NAFLD has been recently re-named as Metabolic dysfunction-Associated Fatty Liver Disease (MAFLD). At present, there are no approved pharmacological treatments for this condition. Vitamin D is a molecule with extensive anti-fibrotic, anti-inflammatory, and insulin-sensitizing properties, which have been proven also in hepatic cells and is involved in immune-metabolic pathways within the gut-adipose tissue-liver axis. Epidemiological data support a relationship hypovitaminosis D and the presence of NAFLD and steatohepatitis (NASH); however, results from vitamin D supplementation trials on liver outcomes are controversial. This narrative review provides an overview of the latest evidence on pathophysiological pathways connecting vitamin D to NAFLD, with emphasis on the effects of vitamin D treatment in MAFLD by a nonsystematic literature review of PubMed published clinical trials. This article conforms to the Scale for Assessment of Narrative Review Articles (SANRA) guidelines. Evidence so far available supports the hypothesis of potential benefits of vitamin D supplementation in selected populations of NAFLD patients, as those with shorter disease duration and mild to moderate liver damage.

64Biochemical and histological changes in rat liver caused by cypermethrin and beta-cyfluthrin.PubMed

Brijender Bhushan, Prabhu N Saxena, Nishi Saxena
Arh Hig Rada Toksikol. 2013;64(1):57-67. doi: 10.2478/10004-1254-64-2013-2184.
Cypermethrin and beta-cyfluthrin are two most widely used multipurpose pyrethroids. After determining their oral LD50 (416.98 mg kg-1 and 354.8 mg kg-1 body weight, respectively), we assessed their hepatotoxicity in Wistar rats following acute (0.1 LD50 for 1 day) and sub-acute (0.1 LD50 for 7, 14, 21 or 28 days) poisoning. The assessment was based on hepatic marker enzymes AST, ALT, LDH, ALP, glycogen, total proteins, total lipids, cholesterol, free fatty acids, and phospholipids. AST, ALT, LDH, total lipids, cholesterol, phospholipids, and free fatty acids in hepatic homogenate increased following pyrethroid stress. In contrast, hepatic proteins, glycogen, and ALP activity decreased due to lysis of structural proteins and leakage of enzymes into the blood stream. Biochemical data were consistent with histological alterations (cytoplasmic vacuolisation, nuclear polymorphism, eccentric nucleus, karyolysis, karyorrhexis, and sinusoidal dilation). Comparatively greater hepatocellular damage was noted in beta-cyfluthrin than in cypermethrin-treated rats, which is probably related to the fluorine atom in beta-cyfluthrin.

65Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice.PubMed

Gladys Ferrere, Laura Wrzosek, Frédéric Cailleux, et al.
J Hepatol. 2017 Apr;66(4):806-815. doi: 10.1016/j.jhep.2016.11.008. Epub 2016 Nov 25.
BACKGROUND & AIMS: Alcoholic liver disease (ALD) is a leading cause of liver failure and mortality. In humans, severe alcoholic hepatitis is associated with key changes to intestinal microbiota (IM), which influences individual sensitivity to develop advanced ALD. We used the different susceptibility to ALD observed in two distinct animal facilities to test the efficiency of two complementary strategies (fecal microbiota transplantation and prebiotic treatment) to reverse dysbiosis and prevent ALD. METHODS: Mice were fed alcohol in two distinct animal facilities with a Lieber DeCarli diet. Fecal microbiota transplantation was performed with fresh feces from alcohol-resistant donor mice to alcohol-sensitive receiver mice three times a week. Another group of mice received pectin during the entire alcohol consumption period. RESULTS: Ethanol induced steatosis and liver inflammation, which were associated with disruption of gut homeostasis, in alcohol-sensitive, but not alcohol resistant mice. IM analysis showed that the proportion of Bacteroides was specifically lower in alcohol-sensitive mice (p<0.05). Principal coordinate analysis showed that the IM of sensitive and resistant mice clustered differently. We targeted IM using two different strategies to prevent alcohol-induced liver lesions: (1) pectin treatment which induced major modifications of the IM, (2) fecal microbiota transplantation which resulted in an IM very close to that of resistant donor mice in the sensitive recipient mice. Both methods prevented steatosis, liver inflammation, and restored gut homeostasis. CONCLUSIONS: Manipulation of IM can prevent alcohol-induced liver injury. The IM should be considered as a new therapeutic target in ALD. LAY SUMMARY: Sensitivity to alcoholic liver disease (ALD) is driven by intestinal microbiota in alcohol fed mice. Treatment of mice with alcohol-induced liver lesions by fecal transplant from alcohol fed mice resistant to ALD or with prebiotic (pectin) prevents ALD. These findings open new possibilities for treatment of human ALD through intestinal microbiota manipulation.

66Gut-Liver Axis, Gut Microbiota, and Its Modulation in the Management of Liver Diseases: A Review of the Literature.PubMed

Ivana Milosevic, Ankica Vujovic, Aleksandra Barac, et al.
Int J Mol Sci. 2019 Jan 17;20(2):395. doi: 10.3390/ijms20020395.
The rapid scientific interest in gut microbiota (GM) has coincided with a global increase in the prevalence of infectious and non-infectivous liver diseases. GM, which is also called "the new virtual metabolic organ", makes axis with a number of extraintestinal organs, such as kidneys, brain, cardiovascular, and the bone system. The gut-liver axis has attracted greater attention in recent years. GM communication is bi-directional and involves endocrine and immunological mechanisms. In this way, gut-dysbiosis and composition of "ancient" microbiota could be linked to pathogenesis of numerous chronic liver diseases such as chronic hepatitis B (CHB), chronic hepatitis C (CHC), alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), development of liver cirrhosis, and hepatocellular carcinoma (HCC). In this paper, we discuss the current evidence supporting a GM role in the management of different chronic liver diseases and potential new therapeutic GM targets, like fecal transplantation, antibiotics, probiotics, prebiotics, and symbiotics. We conclude that population-level shifts in GM could play a regulatory role in the gut-liver axis and, consequently, etiopathogenesis of chronic liver diseases. This could have a positive impact on future therapeutic strategies.

67Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review.PubMed

Federica Di Vincenzo, Angelo Del Gaudio, Valentina Petito, et al.
Intern Emerg Med. 2024 Mar;19(2):275-293. doi: 10.1007/s11739-023-03374-w. Epub 2023 Jul 28.
The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition of the intestinal microbiome and the activity of intercellular connections, regulated by hormones, dietary components, inflammatory mediators, and the enteric nervous system (ENS). Over the years, it has become increasingly evident that maintaining a stable intestinal barrier is crucial to prevent various potentially harmful substances and pathogens from entering the internal environment. Disruption of the barrier is referred to as 'leaky gut' or leaky gut wall syndrome and seems to be characterized by the release of bacterial metabolites and endotoxins, such as lipopolysaccharide (LPS), into the circulation. This condition, mainly caused by bacterial infections, oxidative stress, high-fat diet, exposure to alcohol or chronic allergens, and dysbiosis, appear to be highly connected with the development and/or progression of several metabolic and autoimmune systemic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), neurodegeneration, cardiovascular disease, inflammatory bowel disease, and type 1 diabetes mellitus (T1D). In this review, starting from a description of the mechanisms that enable barrier homeostasis and analyzing the relationship between this complex ecosystem and various pathological conditions, we explore the role of the gut barrier in driving systemic inflammation, also shedding light on current and future therapeutic interventions.

68Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders.PubMed

Daniel M Chopyk, Arash Grakoui
Gastroenterology. 2020 Sep;159(3):849-863. doi: 10.1053/j.gastro.2020.04.077. Epub 2020 Jun 20.
Intestinal barrier dysfunction and dysbiosis contribute to development of diseases in liver and other organs. Physical, immunologic, and microbiologic (bacterial, fungal, archaeal, viral, and protozoal) features of the intestine separate its nearly 100 trillion microbes from the rest of the human body. Failure of any aspect of this barrier can result in translocation of microbes into the blood and sustained inflammatory response that promote liver injury, fibrosis, cirrhosis, and oncogenic transformation. Alterations in intestinal microbial populations or their functions can also affect health. We review the mechanisms that regulate intestinal permeability and how changes in the intestinal microbiome contribute to development of acute and chronic liver diseases. We discuss individual components of the intestinal barrier and how these are disrupted during development of different liver diseases. Learning more about these processes will increase our understanding of the interactions among the liver, intestine, and its flora.

69Intestinal permeability--a new target for disease prevention and therapy.PubMed

Stephan C Bischoff, Giovanni Barbara, Wim Buurman, et al.
BMC Gastroenterol. 2014 Nov 18;14:189. doi: 10.1186/s12876-014-0189-7.
Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms 'intestinal barrier' and 'intestinal permeability' are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by 'intestinal permeability'. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and--more recently recognized--obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.

70Intestinal permeability disturbances: causes, diseases and therapy.PubMed

Barbara Macura, Aneta Kiecka, Marian Szczepanik
Clin Exp Med. 2024 Sep 28;24(1):232. doi: 10.1007/s10238-024-01496-9.
Nowadays, a pathological increase in the permeability of the intestinal barrier (the so-called leaky gut) is increasingly being diagnosed. This condition can be caused by various factors, mainly from the external environment. Damage to the intestinal barrier entails a number of adverse phenomena: dysbiosis, translocation of microorganisms deep into the intestinal tissue, immune response, development of chronic inflammation. These phenomena can ultimately lead to a vicious cycle that promotes the development of inflammation and further damage to the barrier. Activated immune cells in mucosal tissues with broken barriers can migrate to other organs and negatively affect their functioning. Damaged intestinal barrier can facilitate the development of local diseases such as irritable bowel disease, inflammatory bowel disease or celiac disease, but also the development of systemic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, hepatitis, and lupus erythematosus, neurodegenerative or psychiatric conditions, or metabolic diseases such as diabetes or obesity. However, it must be emphasized that the causal links between a leaky gut barrier and the onset of certain diseases often remain unclear and require in-depth research. In light of recent research, it becomes crucial to prevent damage to the intestinal barrier, as well as to develop therapies for the barrier when it is damaged. This paper presents the current state of knowledge on the causes, health consequences and attempts to treat excessive permeability of the intestinal barrier.

71Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction.PubMed

Veronica L Massey, Kendall S Stocke, Robin H Schmidt, et al.
Toxicol Appl Pharmacol. 2015 May 1;284(3):304-14. doi: 10.1016/j.taap.2015.02.022. Epub 2015 Mar 8.
Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9ppm as sodium arsenite) for 10weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects.

72Liver injury from herbal and dietary supplements.PubMed

Victor J Navarro, Ikhlas Khan, Einar Björnsson, et al.
Hepatology. 2017 Jan;65(1):363-373. doi: 10.1002/hep.28813. Epub 2016 Nov 17.
Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (Hepatology 2017;65:363-373).

73Incidence and risk factors of drug-induced liver injury.PubMed

Xiaoyun Li, Jieting Tang, Yimin Mao
Liver Int. 2022 Aug;42(9):1999-2014. doi: 10.1111/liv.15262. Epub 2022 Apr 2.
The epidemiology and aetiology of drug-induced liver injury (DILI) vary across different countries and populations. Overall, DILI is rare in the general population but has become more prevalent in hospitalized patients, especially among patients with unexplained liver conditions. In addition, drugs implicated in DILI differ between Western and Eastern countries. Antibiotics are the leading drugs implicated in DILI in the West, whereas traditional Chinese medicine is the primary cause implicated in DILI in the East. The incidence of herbal and dietary supplements-induced hepatotoxicity is increasing globally. Several genetic and nongenetic risk factors associated with DILI have been described in the literature; however, there are no confirmed risk factors for all-cause DILI. Some factors may contribute to the risk of DILI in a drug-specific manner.

74HERBALIFE® ASSOCIATED SEVERE HEPATOTOXICITY IN A PREVIOUSLY HEALTHY WOMAN.PubMed

Dragan Jurčić, Maruška Gabrić, Rosana Troskot Perić, et al.
Acta Clin Croat. 2019 Dec;58(4):771-776. doi: 10.20471/acc.2019.58.04.26.
Lately there has been an increased consumption of herbal preparations, distributed as nutritional supplements, often claimed to be 'natural' and harmless. However, as their use is not subjected to strict pre-marketing testing and regulations, their ingredients are not clearly defined and there is no quality control or proof of their effectiveness and safety. A growing body of references accentuate their harmful effects, in particular hepatotoxicity, which varies from minimal hepatogram changes to fulminant hepatitis requiring liver transplantation. This case report describes liver damage that was highly suspected to originate from Herbalife® products consumption. We excluded alcohol, viral, metabolic, autoimmune and neoplastic causes of liver lesions, as well as vascular liver disease, but we noticed a connection between the use of Herbalife® products and liver damage. The exact mechanism of liver damage in our patient was not determined. After removing the Herbalife® products, liver damage resolved and there was no need to perform liver biopsy. Taking into consideration the growing consumption of herbal products and their potential harmfulness, we consider that more strict regulations of their production process and sale are necessary, including exact identification of active substances with a list of ingredients, toxicologic testing and obligatory side effect report.

75Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats.PubMed

Mustafa Naziroglu, Aziz Karaoğlu, Asude Orhan Aksoy
Toxicology. 2004 Feb 15;195(2-3):221-30. doi: 10.1016/j.tox.2003.10.012.
Cisplatin is one of the most active cytotoxic agents in the treatment of cancer but its clinical use is associated with nephrotoxicity. Several studies suggest that supplementation with antioxidant can influence cisplatin induced nephrotoxicity. In the present study, we investigated the effect of selenium with high dose vitamin E administration on lipid peroxidation (MDA) and scavenging enzyme activity in kidneys, liver and lens of cisplatin-induced toxicity in rats. Forty female Wistar rats were used. They were randomly divided into five groups. The first and second groups were used as control and cisplatin (6 mg/kg BW) intraperitoneally administrated groups. Groups III, IV and V received intraperitoneally five doses of selenium (1.5 mg/kg BW) and a high dose of vitamin E (1000 mg/kg BW) combination before, simultaneously and after with cisplatin, respectively. Glutathione peroxidase (GSH-Px), vitamin E and beta-carotene levels in the kidney, lens and liver, vitamin A and reduced glutathione (GSH) levels in the kidney were significantly (P<0.05 to <0.001) lower in the cisplatin group than in the control whereas there was a significant increase in kidney, liver and lens MDA levels in rats treated with cisplatin. The decreased antioxidant enzymes and vitamins and increased MDA levels in the kidney, lens and liver of animals administered with cisplatin were significantly (P<0.05 to <0.001) improved with selenium and a high dose vitamin E injection. In conclusion, this data demonstrates that there is an increase in lipid peroxidation in the kidney, liver and lens of animals administered with cisplatin whereas there is a decrease in antioxidant vitamins and enzymes. However, intraperitoneally injected selenium combined with a high dose of vitamin E seem to produce a significant improvement on antioxidants concentrations in rats treated before, simultaneously and after with cisplatin. The selenium with high dose vitamin E injection may play a role in preventing cisplatin-induced nephropathy and cataract formation in cancer patient.

76Targeting increased copper levels in diethylnitrosamine induced hepatocellular carcinoma cells in rats by epigallocatechin-3-gallate.PubMed

Mohd Farhan, Asim Rizvi, Imrana Naseem, et al.
Tumour Biol. 2015 Nov;36(11):8861-7. doi: 10.1007/s13277-015-3649-y. Epub 2015 Jun 12.
We have earlier elucidated a pathway for the anticancer action of plant polyphenolic compounds against malignant cells involving mobilisation of endogenous copper ions and the consequent prooxidant action. To further confirm our hypothesis in vivo, we induced hepatocellular carcinoma (HCC) in rats by diethylnitrosamine (DEN). We show that in such carcinoma cells, there is a progressive elevation in copper levels at various intervals after DEN administration. Concurrently with increasing copper levels, epigallocatechin-3-gallate (EGCG; a potent anticancer plant polyphenol found in green tea) mediated DNA breakage in malignant cells is also increased. The cell membrane permeable copper chelator neocuproine inhibited the EGCG-mediated cellular DNA degradation, whereas the membrane impermeable chelator bathocuproine was ineffective. Iron and zinc specific chelators desferoxamine mesylate and histidine, respectively, were also ineffective in inhibiting EGCG mediated DNA breakage. Through the use of specific scavengers, the mechanism of DNA breakage was determined to be mediated by reactive oxygen species. In summary, we provide an in vivo evidence of accumulating copper in hepatocellular carcinoma that is targeted by EGCG, leading to its anticancer role in a prooxidant manner. Our findings confirm a novel mechanism of anticancer activity of EGCG in particular and plant derived nutraceuticals in general.

77Green tea polyphenol epigallocatechin-3-gallate protects HepG2 cells against CYP2E1-dependent toxicity.PubMed

Jose M Jimenez-Lopez, Arthur I Cederbaum
Free Radic Biol Med. 2004 Feb 1;36(3):359-70. doi: 10.1016/j.freeradbiomed.2003.11.016.
Chronic ethanol consumption causes oxidative damage in the liver, and induction of cytochrome P450 2E1 (CYP2E1) is one pathway involved in oxidative stress produced by ethanol. The hepatic accumulation of iron and polyunsaturated fatty acids significantly contributes to ethanol hepatotoxicity in the intragastric infusion model of ethanol treatment. The objective of this study was to analyze the effect of the green tea flavanol epigallocatechin-3-gallate (EGCG), which has been shown to prevent alcohol-induced liver damage, on CYP2E1-mediated toxicity in HepG2 cells overexpressing CYP2E1 (E47 cells). Treatment of E47 cells with arachidonic acid plus iron (AA + Fe) was previously reported to produce synergistic toxicity in E47 cells by a mechanism dependent on CYP2E1 activity and involving oxidative stress and lipid peroxidation. EGCG protected E47 cells against toxicity and loss of viability induced by AA+Fe; EGCG had no effect on CYP2E1 activity. Prevention of this toxicity was associated with a reduction in oxidative damage as reflected by decreased generation of reactive oxygen species, a decrease in lipid peroxidation, and maintenance of intracellular glutathione in cells challenged by AA+Fe in the presence of EGCG. AA+Fe treatment caused a decline in the mitochondrial membrane potential, which was also blocked by EGCG. In conclusion, EGCG exerts a protective action on CYP2E1-dependent oxidative stress and toxicity that may contribute to preventing alcohol-induced liver injury, and may be useful in preventing toxicity by various hepatotoxins activated by CYP2E1 to reactive intermediates.

78Clinically Relevant Herb-Micronutrient Interactions: When Botanicals, Minerals, and Vitamins Collide.PubMed

Bill J Gurley, Alyssa Tonsing-Carter, Sheila L Thomas, et al.
Adv Nutr. 2018 Jul 1;9(4):524S-532S. doi: 10.1093/advances/nmy029.
The ability of certain foods to impair or augment the absorption of various vitamins and minerals has been recognized for many years. However, the contribution of botanical dietary supplements (BDSs) to altered micronutrient disposition has received little attention. Almost half of the US population uses some type of dietary supplement on a regular basis, with vitamin and mineral supplements constituting the majority of these products. BDS usage has also risen considerably over the last 2 decades, and a number of clinically relevant herb-drug interactions have been identified during this time. BDSs are formulated as concentrated plant extracts containing a plethora of unique phytochemicals not commonly found in the normal diet. Many of these uncommon phytochemicals can modulate various xenobiotic enzymes and transporters present in both the intestine and liver. Therefore, it is likely that the mechanisms underlying many herb-drug interactions can also affect micronutrient absorption, distribution, metabolism, and excretion. To date, very few prospective studies have attempted to characterize the prevalence and clinical relevance of herb-micronutrient interactions. Current research indicates that certain BDSs can reduce iron, folate, and ascorbate absorption, and others contribute to heavy metal intoxication. Researchers in the field of nutrition may not appreciate many of the idiosyncrasies of BDSs regarding product quality and dosage form performance. Failure to account for these eccentricities can adversely affect the outcome and interpretation of any prospective herb-micronutrient interaction study. This review highlights several clinically relevant herb-micronutrient interactions and describes several common pitfalls that often beset clinical research with BDSs.

79Incidence and Etiology of Drug-Induced Liver Injury in Mainland China.PubMed

Tao Shen, Yingxia Liu, Jia Shang, et al.
Gastroenterology. 2019 Jun;156(8):2230-2241.e11. doi: 10.1053/j.gastro.2019.02.002. Epub 2019 Feb 8.
BACKGROUND & AIMS: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. METHODS: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. RESULTS: Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. CONCLUSIONS: In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.

80Drug-induced liver injury: Do we know everything?PubMed

Tamara Alempijevic, Simon Zec, Tomica Milosavljevic
World J Hepatol. 2017 Apr 8;9(10):491-502. doi: 10.4254/wjh.v9.i10.491.
Interest in drug-induced liver injury (DILI) has dramatically increased over the past decade, and it has become a hot topic for clinicians, academics, pharmaceutical companies and regulatory bodies. By investigating the current state of the art, the latest scientific findings, controversies, and guidelines, this review will attempt to answer the question: Do we know everything? Since the first descriptions of hepatotoxicity over 70 years ago, more than 1000 drugs have been identified to date, however, much of our knowledge of diagnostic and pathophysiologic principles remains unchanged. Clinically ranging from asymptomatic transaminitis and acute or chronic hepatitis, to acute liver failure, DILI remains a leading causes of emergent liver transplant. The consumption of unregulated herbal and dietary supplements has introduced new challenges in epidemiological assessment and clinician management. As such, numerous registries have been created, including the United States Drug-Induced Liver Injury Network, to further our understanding of all aspects of DILI. The launch of LiverTox and other online hepatotoxicity resources has increased our awareness of DILI. In 2013, the first guidelines for the diagnosis and management of DILI, were offered by the Practice Parameters Committee of the American College of Gastroenterology, and along with the identification of risk factors and predictors of injury, novel mechanisms of injury, refined causality assessment tools, and targeted treatment options have come to define the current state of the art, however, gaps in our knowledge still undoubtedly remain.

81Drug-induced Liver Injury Secondary to Herbal and Dietary Supplements.PubMed

Elizabeth Zheng, Naemat Sandhu, Victor Navarro
Clin Liver Dis. 2020 Feb;24(1):141-155. doi: 10.1016/j.cld.2019.09.009. Epub 2019 Oct 31.
The use of herbal and dietary supplements (HDS) is increasing in the United States and worldwide. Its significant association with liver injury has become a concern, particularly because rates of hepatotoxicity caused by HDS are increasing. There are variety of HDS available, ranging from multi-ingredient substances, to anabolic steroids for bodybuilding purposes, to individual ingredients for purposes of supplementing a diet. This article reviews the impact of liver injury cause by HDS and explores the hepatotoxic potential of such products and their individual ingredients.

82Estimated Exposure to 6 Potentially Hepatotoxic Botanicals in US Adults.PubMed

Alisa Likhitsup, Vincent L Chen, Robert J Fontana
JAMA Netw Open. 2024 Aug 1;7(8):e2425822. doi: 10.1001/jamanetworkopen.2024.25822.
IMPORTANCE: Use of herbal and dietary supplements (HDSs) accounts for an increasing proportion of drug hepatotoxicity cases. Turmeric or curcumin, green tea extract, Garcinia cambogia, black cohosh, red yeast rice, and ashwagandha are the most frequently reported hepatoxic botanicals, but their prevalence and reasons for use in the general population are unknown. OBJECTIVE: To assess the prevalence and clinical characteristics of adult consumers of 6 potentially hepatoxic botanicals. DESIGN, SETTING, AND PARTICIPANTS: This survey study analyzed nationally representative data from the National Health and Nutrition Examination Survey (NHANES), a nationally representative, cross-sectional survey of the general US population. Prescription drug and HDS exposure data in the past 30 days were analyzed, and 2020 US Census data were used for population estimates. Data were analyzed July 1, 2023, to February 1, 2024. EXPOSURES: Adult NHANES participants enrolled between January 2017 and March 2020. MAIN OUTCOMES AND MEASURES: Baseline weighted characteristics of HDS users and users of 6 potentially hepatotoxic botanical products were compared with non-HDS users. Multivariable analysis was undertaken to identify factors associated with HDS use or at-risk botanical use. RESULTS: Among 9685 adults enrolled in this NHANES cohort, the mean (SE) age was 47.5 (0.5) years, and 51.8% (95% CI, 50.2%-53.4%) were female. The overall prevalence of HDS product use was 57.6% (95% CI, 55.9%-59.4%), while the prevalence of using the 6 botanicals of interest was 4.7% (95% CI, 3.9%-5.7%). Turmeric-containing botanicals were most commonly used (n = 236), followed by products containing green tea (n = 92), ashwagandha (n = 28), Garcinia cambogia (n = 20), red yeast rice (n = 20), and black cohosh (n = 19). Consumers of these 6 botanicals were significantly older (adjusted odds ratio [AOR], 2.36 [95% CI, 1.06-5.25]; P = .04 for 40-59 years of age and AOR, 3.96 [95% CI, 1.93-8.11]; P = .001 for ≥60 years of age), had a higher educational level (AOR, 4.78 [95% CI, 2.62-8.75]; P < .001), and were more likely to have arthritis (AOR, 2.27 [95% CI, 1.62-3.29]; P < .001) compared with non-HDS users. An estimated 15 584 599 (95% CI, 13 047 571-18 648 801) US adults used at least 1 of the 6 botanical products within the past 30 days, which was similar to the estimated number of patients prescribed potentially hepatotoxic drugs, including simvastatin (14 036 024 [95% CI, 11 202 460-17 594 452]) and nonsteroidal anti-inflammatory drugs (14 793 837 [95% CI, 13 014 623-16 671 897]). The most common reason for consuming turmeric and green tea was to improve or maintain health. CONCLUSIONS AND RELEVANCE: In this survey study, an estimated 15.6 million US adults consumed at least 1 botanical product with liver liability within the past 30 days, comparable with the number of people who consumed nonsteroidal anti-inflammatory drugs and a commonly prescribed hypolipidemic drug. Given a lack of regulatory oversight on the manufacturing and testing of botanical products, clinicians should be aware of possible adverse events from consumption of these largely unregulated products.

83Sex disparity and drug-induced liver injury.PubMed

A Floreani, D Bizzaro, S Shalaby, et al.
Dig Liver Dis. 2023 Jan;55(1):21-28. doi: 10.1016/j.dld.2022.06.025. Epub 2022 Jul 15.
Drug-induced liver injury (DILI) is a potentially serious clinical condition that remains a major problem for patients, physicians and those involved in the development of new drugs. Population and hospital-based studies have reported incidences of DILI varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater risk of developing adverse drug reactions and the female/male ratio increases after the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects or interaction with signalling molecules that can influence drug efficacy and safety and differences in abnormal immune response following drug exposure are the main probable causes of the higher vulnerability observed among female patients. A novel phenotype of autoimmune-mediated DILI following the use of check-point inhibitors in oncology and haematology has been recently described. Finally, there have been increasing reports of DILI associated with use of herbal and dietary supplements that is more frequently reported in women.

84The effect of oral nutritional supplementation combined with probiotics on the liver function and intestinal microflora in lung cancer chemotherapy patients through the gut-liver axis.PubMed

Xuelong Li, Wenjing Gong, Kun Tang, et al.
Sci Rep. 2025 Mar 24;15(1):10063. doi: 10.1038/s41598-025-95005-x.
The role of gut microbiota in cancer treatment research is receiving increasing attention. This study aims to evaluate the oral nutritional supplementation combined with probiotics on the liver function and intestinal microflora of lung cancer chemotherapy patients. An evaluation was conducted involving 113 patients with lung cancer, who were given routine hospitalization diet and oral nutrition supplement (ONS). The intervention group received probiotic supplementation, while the control group received placebo. It lasted for 21 days. The primary endpoint was the changes in liver function and intestinal microflora. Secondary endpoints included nutrition and immune status, and blood lipids. Compared with the control group, there were differences in the serum levels of ALT, AST, endotoxin and the amount of gut microbiota in the intervention group (P < 0.05). However, no significant changes were found in nutrition, immune, and the blood lipids status. ONS combined with probiotics could improve the liver function and gut microbiota status of lung cancer chemotherapy patients. We speculate that this may be due to the role of supplementing probiotics in regulating the gut-liver axis.

85Administration of silymarin in NAFLD/NASH: A systematic review and meta-analysis.PubMed

Shudi Li, Fei Duan, Suling Li, et al.
Ann Hepatol. 2024 Mar-Apr;29(2):101174. doi: 10.1016/j.aohep.2023.101174. Epub 2023 Oct 29.
INTRODUCTION AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a high prevalence worldwide and poses serious harm to human health. There is growing evidence suggesting that the administration of specific supplements or nutrients may slow NAFLD progression. Silymarin is a hepatoprotective extract of milk thistle, but its efficacy in NAFLD remains unclear. MATERIALS AND METHODS: Relevant studies were searched in PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrails.gov, and China National Knowledge Infrastructure and were screened according to the eligibility criteria. Data were analyzed using Revman 5.3. Continuous values and dichotomous values were pooled using the standard mean difference (SMD) and odds ratio (OR). Heterogeneity was evaluated using the Cochran's Q test (I statistic). A P<0.05 was considered statistically significant. RESULTS: A total of 26 randomized controlled trials involving 2,375 patients were included in this study. Administration of silymarin significantly reduced the levels of TC (SMD[95%CI]=-0.85[-1.23, -0.47]), TG (SMD[95%CI]=-0.62[-1.14, -0.10]), LDL-C (SMD[95%CI]=-0.81[-1.31, -0.31]), FI (SMD[95%CI]=-0.59[-0.91, -0.28]) and HOMA-IR (SMD[95%CI]=-0.37[-0.77, 0.04]), and increased the level of HDL-C (SMD[95%CI]=0.46[0.03, 0.89]). In addition, silymarin attenuated liver injury as indicated by the decreased levels of ALT (SMD[95%CI]=-12.39[-19.69, -5.08]) and AST (SMD[95% CI]=-10.97[-15.51, -6.43]). The levels of fatty liver index (SMD[95%CI]=-6.64[-10.59, -2.69]) and fatty liver score (SMD[95%CI]=-0.51[-0.69, -0.33]) were also decreased. Liver histology of the intervention group revealed significantly improved hepatic steatosis (OR[95%CI]=3.25[1.80, 5.87]). CONCLUSIONS: Silymarin can regulate energy metabolism, attenuate liver damage, and improve liver histology in NAFLD patients. However, the effects of silymarin will need to be confirmed by further research.

86Curcumin and inflammation in non-alcoholic fatty liver disease: a randomized, placebo controlled clinical trial.PubMed

Saeede Saadati, Amir Sadeghi, Asieh Mansour, et al.
BMC Gastroenterol. 2019 Jul 25;19(1):133. doi: 10.1186/s12876-019-1055-4.
BACKGROUND: The aim of the present study was to evaluate the effects of curcumin supplementation on inflammatory indices, and hepatic features in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Fifty patients with NAFLD were randomized to receive lifestyle modification advice plus either 1500 mg curcumin or the same amount of placebo for 12 weeks. RESULTS: Curcumin supplementation was associated with significant decrease in hepatic fibrosis (p < 0.001), and nuclear factor-kappa B activity (p < 0.05) as compared with the baseline. Hepatic steatosis and serum level of liver enzymes, and tumor necrosis-α (TNF-α) significantly reduced in both groups (p < 0.05). None of the changes were significantly different between two groups. CONCLUSION: Our results indicated that curcumin supplementation plus lifestyle modification is not superior to lifestyle modification alone in amelioration of inflammation. TRIAL REGISTRATION: IRCT20100524004010N24, this trial was retrospectively registered on May 14, 2018.

87Effect of N-acetylcysteine on liver and kidney function tests after surgical bypass in obstructive jaundice: A randomized controlled trial.PubMed

Farzad Kakaei, Masoud Fasihi, Shahriar Hashemzadeh, et al.
Asian J Surg. 2020 Jan;43(1):322-329. doi: 10.1016/j.asjsur.2019.05.009. Epub 2019 Jul 4.
BACKGROUND: It has been shown that N-acetylcysteine may be useful in correcting postoperative hepatic and renal function in many pathological conditions. The present study aimed to examine the effect of N-acetylcysteine on liver and kidney function tests after surgical bypass in patients with obstructive jaundice. METHODS: & Materials: A total of 30 patients with obstructive jaundice who were candidates for bypass surgery were enrolled in this randomized clinical trial. In the case group, intravenous N-acetylcysteine (200 mg/kg per hour in the first 8 h, followed by 100 mg/kg per hour for another 16 h, the same dose for another 24 h) was administered postoperatively. Liver and renal function tests (serum AST, ALT, ALP, GGT, bilirubin, and creatinine) were compared between two groups, as well as duration of hospitalization and ICU stay. RESULTS: Postoperatively, decrease in mean serum AST (p = 0.01), ALT (p = 0.02), ALP (p = 0.01), GGT (p = 0.04) and bilirubin (total, p = 0.02, direct, p = 0.01) levels compared to the preoperative values was significantly more among cases compared to those in controls. Changes in serum creatinine, however, did not differ significantly between two groups (p = 0.18). Hospital and ICU stays were also not different between two study groups (p = 0.27 and p = 0.94 respectively). CONCLUSION: On the basis of our findings, intravenous N-acetylcysteine in patients with obstructive jaundice could significantly preserve liver function after bypass surgery. Effect of this medication on renal function; however, was not statistically significant. TRIAL REGISTRATION: Iranian Registry of Clinical Trial: IRCT2016041016473N7.

88HLA-B*35:01 and Green Tea-Induced Liver Injury.PubMed

Jay H Hoofnagle, Herbert L Bonkovsky, Elizabeth J Phillips, et al.
Hepatology. 2021 Jun;73(6):2484-2493. doi: 10.1002/hep.31538. Epub 2021 May 17.
BACKGROUND AND AIMS: Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS: Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

89Ceftazidime induced liver injury.PubMed

Tayyab Shah, James A Joslyn, James Lai
BMJ Case Rep. 2021 Dec 9;14(12):e246571. doi: 10.1136/bcr-2021-246571.
A 65-year-old woman with type II diabetes mellitus complicated by non-healing ulcers with recurrent osteomyelitis was admitted for progression of cellulitis after treatment failure with an outpatient course of amoxicillin-clavulanate. She was found to have persistent osteomyelitis and started on ceftazidime for a culture documented infection. After two parenteral doses, she had a rapid rise in liver function tests (LFTs) in a hepatocellular pattern. Due to rapid identification, all medications with potential hepatotoxicity, including ceftazidime, were discontinued and the LFTs promptly returned to baseline over 3 days. Of note, the patient did not experience any symptoms of liver injury. Other causes of acute liver injury were effectively ruled out, but the case was confounded by usage of other potential hepatotoxic medications. Still, the most likely culprit was ceftazidime, a rare cause of drug induced liver injury with very few reports in the literature.

90A Case-Report of Drug-Induced Mixed Liver Injury Resulting From Cefepime Exposure.PubMed

Kyle Malhotra, Roman Fazylov, Michelle Friedman-Jakubovics
J Pharm Pract. 2023 Feb;36(1):164-167. doi: 10.1177/08971900211015046. Epub 2021 Jun 8.
A 99-year-old African-American male presented to the hospital with severe sepsis secondary to a urinary tract infection. Upon initial presentation he was tachycardic, hypotensive and had leukocytosis. While he had signs of acute kidney injury, no signs of acute liver injury were present with his alanine transferase (ALT) and amino transferase (AST) levels measuring at 22 and 44 U/L, respectively. During the treatment course the patient began to show signs of clinical improvement. Despite this, his ALT and AST began to increase on day 2 of treatment and reached their peak of 210 and 239 U/L on day 4. Cefepime-induced liver injury was suspected and cefepime was discontinued. Upon cefepime discontinuation, liver enzymes downtrended and gradually returned to normal. No other likely medication causes of liver injury could be identified and alternative medical causes were ruled out. The lack of an alternative cause and the temporal relationship of cefepime use to hepatic dysfunction support the diagnosis of cefepime-induced liver injury. The patient's Roussel Uclaf Causality Assessment Methods score was 7, indicating this was a possible case of cefepime-induced liver injury, and the Naranjo Nomogram score was 5 indicating this was a probable case of cefepime-induced liver injury. While cefepime-induced liver injury is rare, clinicians should be cognizant of the potential for this adverse effect if liver enzyme elevation is detected during cefepime therapy and other common causes have been ruled out.

91Apixaban-induced liver injury.PubMed

Salvador Machlab, Mireia Miquel, Mercedes Vergara, et al.
Rev Esp Enferm Dig. 2019 Feb;111(2):161-163. doi: 10.17235/reed.2018.5877/2018.
The use of new oral anticoagulants such as apixaban is increasing. We present the case of an 85-year-old patient who was diagnosed with mixed profile toxic hepatitis due to apixaban use. An etiological study was negative, except for anti-smooth muscle antibodies, and a liver biopsy ruled out autoimmune hepatitis. The patient was assigned a score of 7 on the CIOMS/RUCAM scale, indicating a probable causality. The liver injury improved after the withdrawal of apixaban. A previous meta-analysis reported that the risk of hepatotoxicity does not increase with the use of apixaban, nor were any cases reported in registry studies. Nonetheless, more than 120 possible cases currently appear in the European pharmacovigilance database (EudraVigilance). We suggest that apixaban should be considered as a possible cause of liver injury.