修回日期: 2022-03-19
接受日期: 2022-03-26
在线出版日期: 2022-04-08
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是全球最常见的慢性肝病, 与肥胖、代谢综合征、2型糖尿病、动脉硬化性心血管疾病以及结直肠肿瘤等的高发密切相关. 抑郁症是一种常见的精神障碍疾病, 此病具有明显的四高特征, 即高发病率、高复发率、高致残率、高自杀率, 严重危害患者身心健康, 降低患者生活质量. 近年来随着对精神心理健康越来越多的关注, NAFLD患者的精神心理健康也逐渐得到了重视, 其中NAFLD与抑郁症的关系是研究的热点之一. 研究显示NAFLD患者中抑郁症发病率高于非NAFLD患者, 抑郁症患者中NAFLD的发生率亦升高, 两者共病机制也有部分研究结果发表. 本文综述了NAFLD与抑郁症的相关性及其共同机制的研究进展, 旨在为两者共病深入研究打下基础, 为两病共患患者的诊治提供依据和研究方向.
核心提要: 非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)患者中抑郁症发病率高于非NAFLD患者, 抑郁症患者中NAFLD的发生率亦升高, 两者发病机制有共同的病理基础, 本文对NAFLD与抑郁症的相关性及共同机制进行了相关阐述.
引文著录: 彭海玲, 刘丽妮, 刘德良, 谭玉勇. 抑郁症和非酒精性脂肪性肝病: 相关性及潜在机制. 世界华人消化杂志 2022; 30(7): 295-302
Revised: March 19, 2022
Accepted: March 26, 2022
Published online: April 8, 2022
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and is closely related to the high incidence of obesity, metabolic syndrome, type 2 diabetes, arteriosclerotic cardiovascular disease, and colorectal tumor. Depression is a common mental disorder that is characterized by high incidence, high recurrence rate, high disability rate, and high suicide rate, which has serious harm to patients' physical and mental health, reduce the quality of life of patients. In recent years, as more and more attention has been paid to mental health of NAFLD patients, the relationship between NAFLD and depression has become one of the hot research topics. Studies have shown that the incidence of depression in NAFLD patients is higher than that in non-NAFLD patients, and the incidence of NAFLD in depressed patients is also higher. Some research results have been published on the mechanism of comorbidity between the two. This paper reviews the research progress on the correlation and common mechanism between NAFLD and depression, aiming to lay a foundation for further research on the comorbidities of NAFLD and depression, and provide a basis and research direction for the diagnosis and treatment of patients with both comorbidities.
- Citation: Peng HL, Liu LN, Liu DL, Tan YY. Depression and non-alcoholic fatty liver disease: Association and potential mechanisms. Shijie Huaren Xiaohua Zazhi 2022; 30(7): 295-302
- URL: https://www.wjgnet.com/1009-3079/full/v30/i7/295.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v30.i7.295
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是指除酒精和其他明确的肝损伤因素所导致的肝细胞内脂肪过度沉积为主要特征的临床病理综合征, 在全球成年人中患病率约为25%[1], 并且被视为代谢综合征的肝脏表现. NAFLD是一种慢性进展性疾病, 包括非酒精性单纯性肝脂肪变、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)、肝硬化及肝癌, 是美国肝脏移植的适应症[2]. NAFLD多无明显症状, 偶有乏力、消化不良和肝区隐痛等非特异性症状. 肥胖和代谢综合征仍然是NAFLD的重要危险因素, 其中代谢综合征包含中心性肥胖和腹部肥胖、2型糖尿病(diabetes mellitus type 2, T2DM)、血脂异常和高血压[3]. 非酒精性脂肪性肝病与进展性肝细胞脂质积累有关, 大多数是甘油三酯, 高达肝脏重量的10％以上[4]. 尽管三分之一的非酒精性脂肪性肝病最终进入非酒精性脂肪性肝炎, 但其是可逆的, 其病理特征是炎症和肝细胞损伤[5]. "多重打击"学说综合了NAFLD发病的各种过程, 如胰岛素抵抗、脂毒性、炎症、细胞因子失衡、肠道菌群失调等, 为NAFLD的发病机制提供了更全面的描述[6]. 有综述显示[7]NAFLD患者患有T2DM的风险明显大于非NAFLD患者, 且这种风险随着NAFLD严重程度不同而不同, 对NAFLD患者采取有效干预措施后, T2DM的患病风险明显降低. NAFLD也增加患者心血管疾病的风险, 伴有晚期肝纤维化的NAFLD患者的死亡率增加了69%, 且几乎全是由心血管疾病引起[8]. 另外, 有数据表明[7]NAFLD患者慢性肾脏病的患病率高于非NAFLD(20%-55% vs 5%-35%), 而且NAFLD的存在和严重程度与慢性肾脏病的分期存在联系. 一项包含33项研究的Meta分析表明[9]NAFLD会显著增加慢性肾脏病的患病率, 且与NAFLD相比, 非酒精性脂肪性肝炎患者慢性肾脏病的发病率和患病率均较高. 值得注意的是, 目前专家们认为NAFLD不能准确地反映非酒精性脂肪性肝病的相关内容, 代谢(功能障碍)相关性脂肪性肝病[metabolic (dysfunction) associated fatty liver disease, MAFLD]被认为更合适[10]. 该标准基于有肝脂肪变的证据之外, 需满足以下三个标准之一: 超重或者肥胖, T2DM以及代谢紊乱[11].
抑郁症以显著而持久的心境低落为主要特征, 常表现为心境低落、思维迟缓、意志活动减退、认知功能损害和躯体症状, 其病因目前尚不十分清楚. 抑郁症的发病机制较为复杂, 有综述[12]从神经元细胞的凋亡和增值、5-HT活性、线粒体功能障碍及神经炎性反应方面进行了总结. 胰岛素抵抗与抑郁症之间的关系也有许多研究, 其与抑郁症之间呈现正相关[13,14], 胰岛素增敏剂对胰岛素抵抗的抑郁症患者有明显改善[15]. 1990年至2017年抑郁症的发病率增加了49.86%[16], 并且有超过五分之一的人有过抑郁症的经历[17-19]. 世界卫生组织预测, 到2030年, 相对于其他疾病, 抑郁症将导致更多人丧失生命. 在15至44岁, 抑郁症已经成为导致残疾的第二大原因[20]. NAFLD和抑郁症的发生有着密切关系, 有研究发现两者存在共同的危险因素, 包括肥胖和T2DM[21,22], NAFLD患者同时处于不同程度的抑郁状态. 一项Meta分析[23]强调了NAFLD患者抑郁症高发的重要危险因素, 包括糖尿病、体重指数和女性. 抑郁症通常与许多慢性病并存, 逐渐使患者健康状态进一步受损[24]. 多项基于社区和人群的研究报告称, 抑郁症患者患代谢综合征的风险增加约2倍[25-27]. 抑郁症在糖尿病人群中也非常普遍, 超过四分之一的1型糖尿病和T2DM患者受到影响[28]. Meta分析[29]也证实了肥胖和抑郁之间的相互关系, 肥胖会增加患抑郁症的风险, 这种现象在美国人中较为明显. 另外, 有证据证明[30]心理健康疾病如抑郁和焦虑与代谢综合征及心血管疾病之间存在着一些联系, 抑郁和焦虑与心血管疾病发生率呈正相关, 抑郁明显增加患心血管疾病的风险约4倍[31], 这种共患病会增加患者心脏死亡率, 重度抑郁症患者的心脏死亡率是轻度抑郁症患者的2倍以上[32].
在一项前瞻性队列研究[33]中发现青少年NAFLD患者抑郁和焦虑的发生率较高, Youssef等人[34]的一项包含567例NAFLD患者的研究发现53%的患者存在亚临床抑郁, 14%存在临床抑郁, 并且抑郁与严重的肝细胞膨胀有关, Choi等人[35]也得出了相同的结论, 在调整了包括年龄、性别及胰岛素抵抗在内的协变量之后, 这种关联更加明显[36]. 除此之外, Tomeno等[37]的研究还发现合并重度抑郁的NAFLD患者的NAFLD评分更高, 血清转氨酶、γ-谷氨酰转肽酶和铁蛋白水平显著升高, 对NAFLD标准治疗、体重减轻和其他参数的反应相较于未合并重度抑郁的NAFLD患者较差. 而Shaheen等人[38]则发现重度抑郁与NAFLD的不良预后无关, 抗抑郁药米氮平会增加失代偿性肝硬化和死亡的风险. 也有研究发现[39]NAFLD患者表现为灰质和白质萎缩, 侧脑室容量扩大, 出现认知障碍的风险约为非NAFLD的4倍. Seo等[40]进行的一项横断面研究, 在排除了心血管疾病及其它危险因素, 发现NAFLD与较低的认知功能相关, 尤其是视觉空间和执行能力方面[41,42]. 但也有学者认为认知功能降低与肝纤维化有关, 而与NAFLD无关[43]. 在对160名患有NAFLD的青少年进行平均3.8年的随访后, 有9.5%被诊断为抑郁症[33]. 另有一项为期10年的研究[44], 19871名NAFLD患者和19871名对照组的抑郁症患病率分别是21.2%和18.2%, 这种相关性和初始抗抑郁药的终点相似, NAFLD患者首次使用抗抑郁药的累计发病率为18.4%, 非NAFLD为15.8%, 7.9%的NAFLD患者和6.9%的对照组被诊断为焦虑, NAFLD是出现抑郁和焦虑的独立危险因素. 在一项研究慢性肝病患者的抑郁情况中, Weinstein等人[45]发现NAFLD患者的抑郁症患病率高于慢性乙型病毒性肝炎患者(27.2% vs 3.7%). 一项涉及10项研究包含2041752名NAFLD患者的Meta分析[23]指出NAFLD患者抑郁症的患病率为18.21%(95% CI: 11.12-28.38%), NASH患者抑郁症的患病率高达40.68%(95%CI: 25.11-58.37%), NAFLD患者发生抑郁的风险明显高于非NAFLD(OR: 1.29, 95%CI: 1.02-1.64, P = 0.03). 最近的一项Meta分析表明[46]NAFLD患者比非NAFLD抑郁症患病风险更高(OR = 1.13, 95%CI: 1.03-1.24, P = 0.007).
与非抑郁症患者相比, 抑郁症患者NAFLD的患病风险明显增高, 一项包含4688名成年人的研究[14]表明抑郁症和NAFLD相关, 抑郁是NAFLD的预测因子. 美国的一项数据分析显示[47]抑郁症患者NAFLD发病率是非抑郁症患者的1.6-2.2倍, 尽管抑郁症患者年龄较大, 并有诸如糖尿病和高血压, 以及较高的总胆固醇和体重指数, 抑郁症仍可能是NAFLD独立的危险因素. 在精神疾病患者中, NAFLD和NASH的发病率较高[48]. Cho等人[49]对142005名韩国成年人进行了长达8.9年的随访研究, 结果表明抑郁与肝脂肪变性风险增加有关, 尤其是肥胖人群. 有Meta分析[46]显示, 与非抑郁症患者相比, 抑郁症患者患NAFLD的风险显著增加(OR = 1.46, 95%CI: 1.15-1.85, P = 0.002). Karaivazoglou等人[50]认为有精神症状和智力受损的青少年肝脂肪样变的风险更大. 纳入16项前瞻性研究的Meta分析[51]指出心理困扰与肝脏疾病死亡率增加显著相关. Liu等人[52]通过对小鼠足部电刺激和约束建立应激模型, 发现小鼠肝脏甘油三酯和总胆固醇升高, 而体重和内脏脂肪含量降低. 2014-2018年间, 来自北京19家精神专科医院的数据[53]指出精神障碍住院患者NAFLD的患病率达17.63%, 抑郁症患者中NAFLD的患病率为12.62%, 低于精神分裂症患者(22.44%)和双相情感障碍患者(17.89%), 使用抗精神病药的患者, 其NAFLD患病率比未使用抗精神病药的高(19.06% vs 13.49%).
NAFLD是复杂的精神和非传染性躯体疾病系统的一部分, 具有共同的发病机制, 基于共同的生活方式和环境风险, 由炎症、氧化应激途径和线粒体功能失调介导[48]. 有报告称[54]高甘油三酯血症与抑郁存在正相关, 而高水平的高密度脂蛋白与抑郁存在负相关关系. 一项基于核磁共振的代谢组学和临床化学相结合的方法, 在NAFLD队列中鉴定近期自我报告抑郁症状的血清学特征, 其准确率超过了60%[55]. Shao等人[56]认为糖皮质激素、肠道菌群和炎症因子均参与NAFLD和抑郁症的病理过程, 且三者之间存在恶性循环.
糖皮质激素调控多种炎症因子和信号通路, 其水平升高不仅可以通过抑制中枢色氨酸羟化酶2的表达减少5-HT的合成[57], 而且对神经形态和齿状回神经形成负面影响从而减少海马体积, 海马体积减少导致下丘脑-垂体-肾上腺(hypothalamic pituitary adrenal, HPA)轴负反馈失调, 糖皮质激素水平进一步升高, 形成恶性循环, 导致抑郁症的发生[58]. 糖皮质激素还会影响海马神经干细胞和神经前体细胞导致神经元凋亡[59]. 也可通过提高糖皮质激素调节激酶1的活性而抑制脑源性神经营养因子导致抑郁[60]. 关于NAFLD, 糖皮质激素也发挥着重要作用, 一方面, 它可通过各种途径导致胰岛素抵抗[56], 如通过丝裂原活化蛋白激酶途径诱导胰岛B细胞凋亡[61], 通过降低胰岛素受体底物1、PI3K/Akt和蛋白激酶B影响胰岛素信号转导[62], 降低葡萄糖转运蛋白1的表达, 减少胰岛素刺激的葡萄糖摄取, 导致胰岛素抵抗[63]. 胰岛素抵抗会导致肝内脂质过量聚集, 导致肝脂肪变[14]. 另一方面, 高水平的糖皮质激素使游离脂肪酸增加, 诱导CYP2E1的产生, 而CYP2E1是活性氧的主要来源, 在NAFLD中, 活性氧含量明显升高, 且与脂肪变性严重程度成正比[64,65]. 过量的糖皮质激素和游离脂肪酸可以提高炎症因子如肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)和白细胞介素-6(interleukin-6, IL-6)的水平, 导致炎症和肝脏坏死[66].
肠道微生物在抑郁症和NAFLD也发挥着作用, 肝-肠轴让肠道微生物与NAFLD之间紧密联系起来, 脑-肠轴是抑郁症和肠道微生物密不可分的机制之一[67]. 肠道菌群失调可促进脂肪在肝脏的积累导致NAFLD和NASH, 促进单糖的肠道吸收, 加速肝脏脂肪生成[68]. 细菌源性产物可诱导脂肪组织炎症、肝脏脂肪变性和肝脏炎症[69]. 肠道菌群与抑郁症的关系主要指向细菌产物介导的炎症失调[70,71]. 与健康对照组相比, 抑郁症患者的肠道菌群生物多样性有所增加, 但双歧杆菌和乳酸杆菌的数量明显低于对照组[72]. 肠道菌群紊乱会增加肠道通透性, 导致脂多糖水平升高, Toll样受体(Toll-like receptors, TLRs)是脂多糖的模式识别受体, 广泛存在于细胞中, 诱导和促进炎症反应[56]. TLR4的激活导致炎症因子TNF-α和IL-6的释放[73], 刺激HPA轴或者抑制其负反馈, 使糖皮质激素释放增加[74]. 除此之外, TLR4的激活使小胶质细胞向M1表型转变, 在中枢系统诱导炎症反应[73], 导致抑郁症[75]. 肠道菌群也可通过色氨酸代谢途径对大脑发挥作用, 肠嗜铬细胞中的色氨酸合成5-HT[76], 由迷走神经向大脑传递信号[77], 触发抑郁行为. 肠道菌群一方面可以通过胆汁酸代谢参与NAFLD的发生与发展[78], 胆汁酸的代谢产物石胆酸可以激活PXR, 而PXR可以诱导肝脏脂肪变性[79]. 另一方面, 肠道菌群的过度生长, 肠壁通透性增加及细菌移位导致大量脂多糖分泌, 随门静脉进入肝脏[56], 其中分泌型脂多糖可激活TLR4, TLR4表达于多种肝脏细胞, 诱导炎症因子的释放, 促进炎症反应, 参与胰岛素抵抗和肝脏脂肪变性和肝细胞凋亡[80].
炎症因子TNF-α、IL-6、IL-8和IL-18在抑郁症和NAFLD中都有高水平表达, 但目前的研究主要集中于TNF-α和IL-6[56]. TNF-α可直接激活HPA轴, 致使糖皮质激素大量分泌[81], 也可通过JNK和NF-κB信号通路导致糖皮质激素受体表达减少和功能下降 [82]. TNF-α可增加下丘脑室旁核对5-HT和去甲肾上腺素的再摄取[83], 引起抑郁症状. IL-6则通过过度激活HPA轴[81], 刺激吲哚胺2, 3-双加氧酶降解色氨酸减少5-HT的合成导致抑郁症[84]. TNF-α在NAFLD中也发挥着重要作用, 它不仅促进细胞损伤和凋亡[85], 还与胰岛素抵抗高度相关, 是第一个与胰岛素抵抗相关的炎症因子[86]. 此外, TNF-α还可以激活SREBP-1c, 上调脂质合成基因的表达诱导肝脏脂肪变性[87]. TNF-α可诱导IL-6的产生[87], IL-6激活JNK、STAT3和ERK通路参与胰岛素抵抗和细胞凋亡[88,89].
综上所述, 目前已有许多研究证明NAFLD与抑郁症之间存在密不可分的关系, 但两者之间的共同机制仍然较为复杂, 炎症因子、糖皮质激素和肠道微生物共同参与其中, 但仍不排除尚有其他因素参与其中. NAFLD可能促进抑郁症的发生, 反之亦然, 形成恶性循环. 只有阐明这些因素的致病机制, 打破这种恶性循环, 才有助于在临床实践中预防和治疗共患NAFLD和抑郁症的患者.
学科分类: 胃肠病学和肝病学
手稿来源地: 湖南省
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科学编辑:张砚梁 制作编辑:张砚梁
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