Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain.
Metab Brain Dis. 2024 Dec;39(8):1667-1677. doi: 10.1007/s11011-024-01417-5. Epub 2024 Aug 23.
Many patients with liver cirrhosis show minimal hepatic encephalopathy (MHE) with mild cognitive impairment (MCI) and motor alterations that reduce their quality of life. Some patients with steatotic liver disease also suffer MCI. To design treatments to improve MHE/MCI it is necessary to understand the mechanisms by which liver disease induce them. This review summarizes studies showing that appearance of MHE/MCI is associated with a shift in the immunophenotype leading to an "autoimmune-like" form with increased pro-inflammatory monocytes, enhanced CD4 T and B lymphocytes activation and increased plasma levels of pro-inflammatory cytokines, including IL-17, IL-21, TNFα, IL-15 and CCL20. The contribution of peripheral inflammation to trigger MHE is supported by studies in animal models and by the fact that rifaximin treatment reverses MHE in around 60% of patients in parallel with reversal of the changes in peripheral inflammation. MHE does not improve in patients in which peripheral inflammation is not improved by rifaximin. The process by which peripheral inflammation induces MHE involves induction of neuroinflammation in brain, with activation of microglia and astrocytes and increased pro-inflammatory TNFα and IL-1β, which is observed in patients who died with steatotic liver disease (SLD) or liver cirrhosis and in animal models of MHE. Neuroinflammation alters glutamatergic and GABAergic neurotransmission, leading to cognitive and motor impairment. Transmission of peripheral alterations into the brain is mediated by infiltration in brain of extracellular vesicles from plasma and of cells from the peripheral immune system. Acting on any step of the process peripheral inflammation - neuroinflammation - altered neurotransmission may improve MHE.
许多肝硬化患者表现出轻微的肝性脑病 (MHE)，伴有轻度认知障碍 (MCI) 和运动改变，从而降低了他们的生活质量。一些脂肪性肝病患者也患有 MCI。为了设计改善 MHE/MCI 的治疗方法，有必要了解导致肝性脑病的发病机制。这篇综述总结了表明 MHE/MCI 出现与免疫表型转变相关的研究，导致出现具有增加的促炎单核细胞、增强的 CD4 T 和 B 淋巴细胞激活以及增加的促炎细胞因子（包括 IL-17、IL-21、TNFα、IL-15 和 CCL20）的“自身免疫样”形式。外周炎症导致 MHE 的发病机制得到了动物模型研究和利福昔明治疗约 60%的 MHE 患者逆转的事实的支持，同时外周炎症的变化也得到了逆转。在利福昔明不能改善外周炎症的患者中，MHE 不会改善。外周炎症诱导 MHE 的过程涉及到脑内的神经炎症，观察到在患有脂肪性肝病 (SLD) 或肝硬化的患者和 MHE 的动物模型中，小胶质细胞和星形胶质细胞的激活以及促炎 TNFα 和 IL-1β 的增加。神经炎症改变了谷氨酸能和 GABA 能神经传递，导致认知和运动障碍。外周改变向大脑的传递是通过来自血浆的细胞外囊泡和来自外周免疫系统的细胞在大脑中的渗透介导的。作用于外周炎症 - 神经炎症 - 改变神经递质传递的任何步骤都可能改善 MHE。
