孙超主任/崔膑心医师团队发现：肝硬化患者中脂质/脂蛋白水平异常的临床意义（下篇）

2019年肝病领域顶刊JOH指出，世界范围内每年大约有200万例患者死于肝脏疾病，我国约有700万肝硬化患者，每年新发肝癌46万，乙丙肝感染者逾1亿，为社会带来沉重的医疗和经济负担。

为契合《“健康中国2030”规划纲要》中提出的将重大慢性疾病过早死亡率较2015年下降30%的目标，肝胆相照平台与天津医科大学总医院消化内科联合打造“肝研撷萃”精品栏目。

“肝研撷萃”由天津医科大学总医院孙超主任担任总编辑，范晓飞博士、惠洋洋博士、王晓雨博士、崔膑心博士任执行编辑，通过研读分享各种肝脏疾病诊断、治疗、预防和发病机制的前沿进展，结合团队自身的工作，为广大医生提供精进学术、助力临床的交流平台。

肝脏在脂质/脂蛋白的代谢转化和运输过程中发挥着重要作用。脂质/脂蛋白与肝硬化的病理过程、疾病进展、并发症的出现和治疗反应密切相关。孙超主任课题组总结了不同类型肝硬化背景下脂质代谢变化的潜在机制。最新证据表明，血脂异常与肝硬化的发病和死亡风险有密切的联系。因此，结合血脂水平对肝硬化患者进行风险分层评估，制定最佳的治疗策略具有重要的临床意义。2022年9月，这一领域相关成果以综述的形式发表在“Gene Expression The Journal of Liver Research”。

“肝研撷萃”第十五、十六期，孙超主任团队对该综述进行分享，以启迪临床。本期分享高密度脂蛋白（HDL）相关的生物标志物预测肝硬化并发症、 HDL相关的生物标志物预测死亡。

作者：崔膑心 刘俊玲 孙超

单位：1. 天津医科大学总医院 消化内科

2. 天津医科大学总医院空港医院 消化科

HDL相关的生物标志物预测肝硬化并发症

1 上消化道出血

上消化道出血是临床常见的一种危重急症，发病率和死亡率高。Hrabovsky等发现急性上消化道出血患者的血清总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）和高密度脂蛋白胆固醇（HDL-C）水平显著降低，并且肝硬化和非肝硬化患者的血脂谱除了HDL-C外没有显著差异35。作者认为急性上消化道出血患者的血脂合成和吸收过程可能均发生了改变，而出血早期的禁食导致了与胆固醇吸收有关标志物的低表达。此外，患者的血浆植物甾醇的浓度较低，也表明肝硬化患者的胆固醇吸收发生了变化。

胰岛素抵抗是HCV感染过程中的一种早期现象，与肝纤维化的发病机制密切相关，而且胰岛素抵抗与食管静脉曲张的进展有关。一项纳入100例无糖尿病及代谢综合征的代偿期丙肝肝硬化患者的研究结果显示，胰岛素/HDL-C比值为0.147时提示食管静脉曲张的发生率增加，诊断准确性为0.82236。相似地，Hanafy等报道极低密度脂蛋白（VLDL）<16.5mg/dL及低密度脂蛋白（LDL）/血小板比值>1时，丙肝肝硬化患者发生进展期纤维化、食管静脉曲张及内皮功能障碍的风险增加37。

此外，一项研究发现HDL-C水平≤0.54 mmol/L可预测乙肝肝硬化合并急性消化道出血患者的6周死亡率38。作者提出：首先，HDL-C是反映肝功能的生物标志物，因贫血和低血压引起的肝细胞缺血可能会导致HDL-C水平显著降低；其次，体外实验已证实HDL-C参与了对内源性和外源性凝血级联反应的调节39。

2 门静脉高压

肝硬化合并门静脉血栓形成患者的预后不佳。据报道，HDL-C与肝硬化合并门静脉血栓形成患者的1年死亡率独立相关40。一项前瞻性队列研究纳入77例因门静脉高压症而接受脾切除术的患者，结果表明术后的脂蛋白（a）水平是门静脉和/或脾静脉血栓形成（PSVT）的可靠预测指标41。此外，与没有PSVT的患者相比，PSVT患者在术后有更高的脂蛋白（a）水平。

3 细菌感染

细菌感染是肝硬化患者再入院的常见原因，发病率为25%-46%42,43，常见的感染主要包括自发性细菌性腹膜炎（SBP）和尿路感染。大量证据表明，免疫功能降低可促进细菌感染的进展44,45。菌群失调如肠球菌/变形菌门的富集和有益的毛螺菌门减少，均与肝硬化的进展有关46。此外，肠球菌和革兰氏阴性菌（绿脓杆菌、肺炎克雷伯杆菌和大肠杆菌）是通过病理性易位引起SBP的常见致病菌47。糖尿病和低水平的HDL-C是乙肝肝硬化患者发生细菌感染的危险因素48。然而，糖尿病和肝硬化共同影响细菌感染的发病机制尚不明确。有学者提出，高血糖会扰乱免疫系统内稳态，并为细菌生长提供有利的微环境49，而HDL-C可通过清除胆固醇颗粒来抑制巨噬细胞介导的炎症反应50。

4 相对肾上腺皮质功能不全 

最近的研究表明，肝硬化可以导致相对肾上腺皮质功能不全（RAI），RAI患者更易出现细菌感染、败血症、肝外器官衰竭和ACLF51。虽然RAI的发病机制尚不明确，但胆固醇代谢紊乱可能发挥重要作用。肝硬化患者的血清皮质醇水平显著低于非肝硬化患者52。RAI通过影响肝脏的合成、代谢和功能储备，与肝功能障碍的严重程度及患者死亡率的增加密切相关，最终导致不良预后。

Piano等发现HDL-C水平降低与急性失代偿期肝硬化患者发生RAI独立相关51。作者认为HDL-C可能是导致肝硬化中类固醇生成底物缺乏的原因。此外，他们提出炎症细胞因子可能直接影响肾上腺，或在受体水平上与促肾上腺皮质激素（ACTH）竞争，从而阻碍类固醇的产生53。

Wentworth等指出，失代偿期肝硬化患者中HDL-C水平降低、卵磷脂胆固醇酰基转移酶（LCAT）活性下降，胆固醇代谢障碍可导致肾上腺产生类固醇的底物不足，进而促进RAI的发展54。

HDL相关的生物标志物预测死亡

在一项纳入191例患者的回顾性队列研究中，TC是肝硬化死亡率的重要预测因子，将胆固醇添加到传统的肝硬化评分系统，即终末期肝病模型（MELD）评分，能够将预测准确性提高3%5。Trieb等发现HDL-C<17mg/dl（0.44mmol/L）和apoA-I<50mg/dl可预测肝硬化患者90天死亡率24。另一项研究也证实了HDL-C≤0.53mmol/L是乙肝肝硬化失代偿期患者30天死亡率的独立预测因素6，进一步的受试者工作特性曲线分析显示HDL-C与MELD评分的预测价值相似。值得注意的是，Cui等使用倾向得分匹配分析来评估HDL-C对短期死亡率的预测价值4。结果表明HDL-C<0.4mmol/L预示肝硬化患者180天死亡风险较高。此外，HDL-C较MELD评分及Child-Pugh分级有更佳的预测价值。

众所周知，炎症反应是进展期肝硬化患者的常见特征，意味着较差的预后55。单核细胞与HDL-C的比率是最近提出的一种炎症生物标志物，比率升高预示失代偿期乙肝肝硬化患者的死亡风险增加56。潜在机制包括炎症反应触发单核细胞释放到外周血并产生促炎分子，加剧反应程度和不良结局57。同时，HDL-C作为一种抗炎脂蛋白，能够结合并中和细菌脂多糖，从而促进它们的排出58。

具有肝毒性的脂蛋白Z是一种异常的富含游离胆固醇的LDL样颗粒，在普通人群中基本检测不出血浆脂蛋白Z。相反，一项研究发现，脂蛋白Z在30.8%的移植前肝硬化患者中可检测到59。肝硬化患者有低水平的循环LCAT，这可能是脂蛋白Z产生的原因。作者还发现脂蛋白Z与更差的Child-Pugh分级和更高的MELD评分有关，从而导致肝硬化患者的死亡率增加。

结  论

综上所述，我们总结了血清脂质/脂蛋白在肝硬化发展和预后中的潜在作用，以及它们表达水平异常的可能机制。虽然目前血脂与肝硬化的关系已得到广泛的研究，然而，肝硬化患者中脂质/脂蛋白变化的临床意义仍需进一步的阐明，以优化疾病风险分层和治疗策略。

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作者简介

崔膑心

天津医科大学总医院空港医院消化科主治医师、博士在读，硕士毕业于天津医科大学。以第一/共同第一作者身份在Pharmacological research, Journal of Clinical Lipidology和 Digestion等SCI期刊发表论文近10篇，单篇最高影响因子10.334。目前研究方向为慢性肝病与血脂代谢紊乱、体成分异常之间的关系。

专家简介

孙超

副主任医师，本科毕业于北京大学医学部，天津医科大学医学/理学博士，日本兵库医科大学研究员。全国疑难及重症肝病攻关协作组成员。主持完成国家自然科学基金一项。担任SCI期刊Journal of Clinical and Translational Hepatology编委、2021年度杰出编委，Gene Expression The Journal of Liver Research编委，任职Portal Hypertension & Cirrhosis首届学术委员会。2020年在EASL（欧洲肝脏研究学会）年会做口头发言，2021年在AASLD（美国肝病研究协会）年会做壁板展示。获得EASL的“Full Bursary”和APDW的“Travel Grant”奖励。以通讯作者在Clinical Nutrition, Liver International, Cell Death & Disease, Hepatology Communications等杂志发表SCI文章50余篇，他引670余次，h指数16，研究成果被ASGE（美国胃肠内镜学会）和EASL发布的临床实践指南引用。目前研究方向为调节性细胞死亡在急慢性肝损伤中的作用机制，体成分异常、营养不良、衰弱、睡眠障碍以及微量元素对肝硬化预后的影响及干预措施。

本文仅供医疗卫生专业人士为了解资讯使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议。如该等信息被用于了解资讯以外的目的，平台及作者不承担相关责任。