Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT 06510, USA.
Second Department of Liver Disease Center, Youan Hospital, Capital Medical University, Beijing, 100069, China.
EBioMedicine. 2023 Jul;93:104679. doi: 10.1016/j.ebiom.2023.104679. Epub 2023 Jun 23.
Chronic liver diseases of all etiologies exist along a spectrum with varying degrees of hepatic fibrosis. Despite accumulating evidence implying associations between liver fibrosis and cognitive functioning, there is limited research exploring the underlying neurobiological factors and the possible mediating role of inflammation on the liver-brain axis.
Using data from the UK Biobank, we examined the cross-sectional association of liver fibrosis (as measured by Fibrosis-4 score) with cognitive functioning and regional grey matter volumes (GMVs) while adjusting for numerous covariates and multiple comparisons. We further performed post-hoc preliminary analysis to investigate the mediating effect of C-reactive protein (CRP) on the association between liver fibrosis and both cognitive functioning and GMVs.
We analysed behaviour from up to 447,626 participants (N ranged from 45,055 to 447,533 per specific cognitive metric) 37 years and older. 38,244 participants (age range 44-82 years) had GMV data collected at a median 9-year follow-up. Liver fibrosis showed significant associations with cognitive performance in reasoning, working memory, visual memory, prospective memory, executive function, and processing speed. Subgroup analysis indicated larger effects sizes for symbol digital substitution but smaller effect sizes for trail making in middle-aged people than their old counterparts. Neuroimaging analyses revealed significant associations between liver fibrosis and reduced regional GMVs, primarily in the hippocampus, thalamus, ventral striatum, parahippocampal gyrus, brain stem, and cerebellum. CRP levels were significantly higher in adults with advanced liver fibrosis than those without, indicating an elevated systemic inflammation. Moreover, the serum CRP significantly mediated the effect of liver fibrosis on most cognitive measures and regional GMVs in the hippocampus and brain stem.
This study provides a well-powered characterization of associations between liver fibrosis, cognitive impairment, and grey matter atrophy. It also highlights the possibly mediating role of systemic inflammation on the liver-brain axis. Early surveillance and prevention of liver diseases may reduce cognitive decline and brain GMV loss.
National Science Foundation, and National Institutes of Health.
各种病因导致的慢性肝脏疾病存在一个连续谱，其肝纤维化程度也各不相同。尽管有越来越多的证据表明肝纤维化与认知功能之间存在关联，但关于潜在的神经生物学因素以及炎症在肝脑轴上的可能介导作用的研究仍很有限。
我们利用英国生物库的数据，在调整了许多协变量和多次比较后，研究了肝纤维化（通过 Fibrosis-4 评分来衡量）与认知功能和局部灰质体积（GMV）之间的横断面关联。我们还进行了事后初步分析，以探讨 C 反应蛋白（CRP）在肝纤维化与认知功能和 GMV 之间的关联中的介导作用。
我们分析了多达 447626 名参与者（每项特定认知指标的 N 值范围为 45055 至 447533）的行为，这些参与者的年龄在 37 岁及以上。38244 名参与者（年龄在 44-82 岁之间）在中位数为 9 年的随访中采集了 GMV 数据。肝纤维化与推理、工作记忆、视觉记忆、前瞻性记忆、执行功能和处理速度等认知表现有显著关联。亚组分析表明，符号数字替代测试的效应大小较大，但中年人的追踪测试的效应大小较小，而老年人则相反。神经影像学分析显示，肝纤维化与海马体、丘脑、腹侧纹状体、海马旁回、脑干和小脑等部位的 GMV 减少有显著关联。肝纤维化程度较高的成年人的血清 CRP 水平明显高于无肝纤维化的成年人，表明全身炎症水平升高。此外，血清 CRP 显著介导了肝纤维化对大多数认知指标和海马体及脑干 GMV 的影响。
本研究充分描述了肝纤维化、认知障碍和灰质萎缩之间的关联，并强调了全身炎症在肝脑轴上的可能介导作用。早期对肝脏疾病的监测和预防可能会减少认知能力下降和大脑 GMV 损失。
美国国家科学基金会和美国国立卫生研究院。
