非酒精性脂肪性肝病与抑郁症关系的系统评价及Meta分析

Association between non-alcoholic fatty liver disease and depression： A systematic review and Meta-analysis

摘要

目的 系统评价非酒精性脂肪性肝病（NAFLD）与抑郁症的关联性，为临床协同管理提供依据。 方法 本研究根据PRISMA指南完成，PROSPERO注册号：CRD42023482013。检索PubMed、Embase、Cochrane Library、Web of Science、中国知网、万方、维普、CBM数据库建库至2024年11月1日公开发表的NAFLD和抑郁症二者相关性的研究文献，根据纳入和排除标准筛选文献并提取数据。采用RevMan 5.3进行Meta分析。 结果 共纳入18项研究，涉及396 793例参与者。12项研究探讨NAFLD对抑郁症的影响，共涉及224 269例参与者，其中包含75 574例NAFLD患者。Meta分析显示，NAFLD显著增加抑郁症发生风险（OR=1.21，95%CI： 1.12～1.30，P0.001）。6项研究分析抑郁症对NAFLD的影响，共涉及172 524例参与者，其中包含29 368例抑郁症患者。Meta分析显示，抑郁症导致NAFLD风险显著增加（OR=1.13，95%CI： 1.05～1.22，P=0.001）。 结论 NAFLD与抑郁症存在显著的双向关联。在初诊和随访时，建议对NAFLD患者行抑郁症筛查并加强心理健康监测；对抑郁症患者需重视代谢功能评估并实施运动干预。

Abstract

Objective To systematically review the association between non-alcoholic fatty liver disease （NAFLD） and depression， and to provide a basis for synergistic management in clinical practice. Methods This study was conducted according to the PRISMA guidelines， with the PROSPERO registration number of CRD42023482013. PubMed， Embase， the Cochrane Library， Web of Science， CNKI， Wanfang Data， VIP， and CBM were searched for articles on the association between NAFLD and depression published up to November 1， 2024. The articles were screened according to the inclusion and exclusion criteria， and related data were extracted. RevMan 5.3 was used to perform the Meta-analysis. Results A total of 18 studies were included， involving 396 793 participants. Among these studies， 12 discussed the influence of NAFLD on depression， involving 224 269 participants， among whom there were 75 574 patients with NAFLD. The Meta-analysis showed that NAFLD was significantly associated with the risk of depression （odds ratio ［OR］=1.21， 95% confidence interval ［CI］： 1.12 — 1.30， P0.001）. Six studies examined the influence of depression on NAFLD， involving 172 524 participants， among whom there were 29 368 patients with depression. The meta-analysis showed that depression caused a significant increase in the risk of NAFLD （OR=1.13， 95%CI： 1.05 — 1.22， P=0.001）. Conclusion There is a significant bidirectional association between NAFLD and depression. It is recommended to perform the screening for depression and enhance mental health monitoring in patients with NAFLD， and metabolic function assessment and exercise intervention should be performed for patients with depression.

Graphical abstract

关键词

非酒精性脂肪性肝病 / 抑郁症 / Meta分析

Key words

Non-Alcoholic Fatty Liver Disease / Depressive Disorder / Meta-Analysis

非酒精性脂肪性肝病（non-alcoholic fatty liver disease，NAFLD）是一种与胰岛素抵抗和遗传易感性密切相关的代谢应激性肝损伤^［1］，其患病率呈逐年上升趋势。据估算，至2030年NAFLD的全球疾病负担将增加2～3倍^［2］。目前尚无针对NAFLD的治疗方法，因此明确NAFLD及其进展的可调控危险因素至关重要^［3］。抑郁症是一种常见的致残性情绪障碍，可导致认知、情绪和躯体功能受损^［4］。全球疾病负担研究显示，2030年抑郁症的年龄标准化发病率预计将达到男性2 519.88/10万、女性3 835.11/10万^［5］。尽管现有多种治疗手段，抑郁症患者仍面临症状反复发作的困扰，严重影响生活质量^［6］。

NAFLD与抑郁症共享肥胖、代谢综合征、2型糖尿病及心血管疾病等危险因素，这些因素可协同增加NAFLD的患病风险^［7-9］。多项研究表明，抑郁症患者发生代谢综合征的风险是普通人群的2倍^［10-12］。因此，相关指南推荐对所有抑郁症患者常规筛查超重/肥胖^［13］。同时，NAFLD患者中抑郁症的患病率亦显著升高^［14］。胰岛素抵抗既是NAFLD的核心病理特征，也是抑郁症患者常见的状态依赖性代谢异常^［15］，其可能通过干扰抑郁相关脑区功能，成为二者关联的潜在机制^［16］。尽管现有证据提示NAFLD与抑郁症密切相关，但尚缺乏系统评价研究。本研究采用Meta分析方法，系统评价NAFLD与抑郁症的关联性，旨在为临床协同防治提供循证依据。

1 资料与方法

1.1 规程与注册

本研究严格遵循系统评价和Meta分析优先报告条目（PRISMA）声明^［17］。研究方案已于PROSPERO国际前瞻性系统评价注册平台完成注册，注册号：CRD42023482013。

1.2 文献检索策略

检索PubMed、Embase、Cochrane Library、Web of Science、中国知网、万方、维普、CBM数据库建库至2024年11月1日公开发表的NAFLD和抑郁症二者相关性的研究文献。使用与“非酒精性脂肪性肝病”和“抑郁症”相关的中英文搜索词，采用主题词与自由词相结合的检索方法。中文检索主题词分别为非酒精性脂肪性肝病和抑郁症，自由词为：非酒精性脂肪肝、非酒性脂肪肝、非酒精性脂肪肝病、单纯性脂肪肝、非乙醇性脂肪肝、非乙醇性脂肪性肝病、非酒精性脂肪性肝病、非酒精性肝病；抑郁症、抑郁性神经症、神经症性抑郁、抑郁性障碍、抑郁障碍、抑郁障碍症。英文检索主题词分别为nonalcoholic fatty liver disease、depression。自由词为：nonalcoholic fatty liver、NAFLD、nonalcoholic fatty liver disease、non alcoholic fatty liver disease、non alcoholic hepato-steatosis、non alcoholic hepatosteatosis、non alcoholic liver steatosis、non alcoholic steatotic hepatopathy、non-alcoholic fatty liver、non-alcoholic fatty liver disease等；clinical depression、depressive disease、depressive disorder、depressive episode、depressive illness等。

1.3 纳入标准

（1）研究类型：前瞻性或回顾性的观察性研究；（2）抑郁症诊断：符合《美国精神病学会精神障碍诊断与统计手册》（DSM）标准或《国际疾病和相关健康问题统计分类（第十版）》疾病代码F32～F33或抑郁症筛查工具报告标准；（3）NAFLD诊断：符合肝活检或放射学、腹部超声等影像学检查诊断标准。

1.4 排除标准

（1）重复发表或无法获取全文的文献；（2）非中或英文文献；（3）会议摘要、病例报告、综述、信函、评论及临床指南类文献；（4）无法提取有效数据的文献。

1.5 文献筛选与数据提取

研究由3位研究者独立检索和筛选。首先根据标题和摘要进行初筛，再依据纳入标准对潜在研究进行全文评估。研究者对筛选结果进行交叉核对，通过讨论和投票解决分歧。数据提取内容包括：第一作者、发表年份、国家、样本量、研究对象特征、年龄分布、研究设计类型、效应量指标［优势比（OR）、风险比（HR）、相对风险（RR）及其95％可信区间（95%CI）］、校正变量等关键信息。

1.6 文献质量评价

采用纽卡斯尔-渥太华量表（NOS）评估纳入研究的质量^［18］，该量表满分为9分，评分≥6分视为高质量研究，6分为低质量研究。3位研究者独立完成质量评价后，通过讨论协商解决评分差异。

1.7 统计学方法

使用RevMan 5.3软件进行Meta分析。基于NAFLD和抑郁症的全球患病率（分别为25%和4.4%）^［19-20］，选择OR作为主要效应量指标。对于以抑郁症为结局的研究直接采用OR值；对于以NAFLD为结局的研究，采用公式OR=（1-P0）×RR/（1-P0×RR）将RR/HR转换为OR^［21］，其中P0为结局事件发生率。多因素分析中优先选择校正最充分的模型。根据数据可获得性，按亚洲和欧美地区进行亚组分析。采用Q检验和I²统计量评估异质性：I²50%时选用固定效应模型，I²≥50%时选用随机效应模型。通过敏感性分析探讨异质性来源，当纳入研究超过10项时采用漏斗图评估发表偏倚。P0.05为差异有统计学意义。

2 结果

2.1 文献筛选结果

通过系统检索共获得1 546篇文献（截至2024年11月1日），经筛选后最终纳入18项研究（图1）。

2.2 纳入文献基本特征及质量评价

18项研究共纳入396 793例研究对象，其中12项研究^［22-33］探讨NAFLD对抑郁症的影响，6项研究^［34-39］分析抑郁症对NAFLD的影响（表1）。质量评价显示纳入研究总体质量中等至较高。多数研究未明确说明随访方法，导致该方面证据质量有所降低。

2.3 NAFLD对抑郁症风险的影响

12项研究^［22-33］纳入224 269例研究对象（NAFLD患者75 574例）分析NAFLD与抑郁症的关联。异质性检验（I²=65%）提示采用随机效应模型。Meta分析显示，NAFLD显著增加抑郁症风险（OR=1.21，95%CI：1.12～1.30，P0.001）（图2）。排除研究^［28］后进行亚组分析，亚洲地区（OR=1.21，95%CI：1.05～1.40）与欧美地区（OR=1.22，95%CI：1.10～1.36）差异无统计学意义（P=0.96）（图3）。

2.4 抑郁症对NAFLD风险的影响

6项研究^［34-39］纳入172 524例研究对象（抑郁症患者29 368例）。异质性检验（I²=75%）提示采用随机效应模型。Meta分析显示，抑郁症显著增加NAFLD风险（OR=1.13，95%CI：1.05～1.22，P=0.001）（图4）。亚组分析显示，亚洲地区（OR=1.24，95%CI：1.06～1.45）与欧美地区（OR=1.22，95%CI：0.87～1.71）差异无统计学意义（P=0.94）（图5）。

2.5 敏感性分析与发表偏倚分析

采用逐一剔除研究法进行敏感性分析，结果显示合并效应量保持稳定，提示结果稳健。异质性可能源于各研究采用的诊断和评估方法不同。由于抑郁症对NAFLD影响的研究不足10项，未进行发表偏倚评估。NAFLD对抑郁症影响的漏斗图对称性良好，提示无明显发表偏倚（图6）。

3 讨论

本研究通过系统评价证实NAFLD与抑郁症存在显著的双向关联。Meta分析结果显示，NAFLD患者发生抑郁症的风险增加21%，而抑郁症患者发生NAFLD的风险增加13%。既往研究结果与本研究结论一致。NAFLD作为代谢综合征在肝脏的表现，与抑郁症存在共同的病理生理基础。现有证据表明，代谢综合征与抑郁、焦虑等精神障碍具有直接相关性^［40-42］。其中，肥胖等代谢异常因素可通过诱发体像障碍和社会歧视增加抑郁风险^［43］。从机制上而言，NAFLD进展过程中释放的促炎细胞因子和趋化因子可能通过干扰神经递质合成和信号传导促进抑郁行为^［44-45］。

全球疾病负担数据显示，精神-躯体共病现象日益突出^［46-47］，NAFLD/NASH（非酒精性脂肪性肝炎）与精神障碍共病尤为显著^［48］。抑郁症可使代谢综合征风险增加1倍，这与抑郁相关的不良健康行为（如运动减少、情绪化饮食）密切相关^［49-50］。此外，精神科药物（抗抑郁药、抗精神病药等）对体质量和能量代谢的影响可能加重NAFLD/NASH的发生发展，在儿童患者中的表现尤为明显^［51-54］。抑郁症相关的慢性炎症状态（表现为CRP、TNF-α、IL-6等炎症标志物升高）也被认为参与肝损伤进程^［55］。

本研究存在以下局限性：（1）纳入研究采用的诊断标准和评估工具存在差异，可能是异质性的主要来源；（2）受研究数量限制，仅完成地域亚组分析（亚洲vs欧美），未能进行年龄、性别等分层分析，其中两项研究提示性别可能是重要影响因素^{［32， 37］}；（3）部分研究随访资料不完整，影响证据质量。未来研究需采用标准化诊断方法、延长随访时间，并加强人口学特征的分层分析。

本研究在临床层面证实了NAFLD与抑郁症之间存在双向关联。NAFLD患者发生抑郁症的风险显著增加，同时抑郁症也是NAFLD发生的重要危险因素。基于上述结论，建议临床实践中对NAFLD患者在初诊和随访时进行抑郁症筛查，加强心理健康监测；对抑郁症患者应重视代谢指标评估和运动干预。未来研究可进一步深入探讨NAFLD与抑郁症发生发展的共同病理生理机制。

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