The neurogliovascular unit in hepatic encephalopathy

Wouter Claeys; Lien Van Hoecke; Sander Lefere; Anja Geerts; Xavier Verhelst; Hans Van Vlierberghe; Helena Degroote; Lindsey Devisscher; Roosmarijn E Vandenbroucke; Christophe Van Steenkiste

doi:10.1016/j.jhepr.2021.100352

The neurogliovascular unit in hepatic encephalopathy

JHEP Rep. 2021 Aug 11;3(5):100352. doi: 10.1016/j.jhepr.2021.100352. eCollection 2021 Oct.

Authors

Wouter Claeys^{1

2

3}, Lien Van Hoecke^{2

3}, Sander Lefere^{1

4}, Anja Geerts¹, Xavier Verhelst¹, Hans Van Vlierberghe¹, Helena Degroote¹, Lindsey Devisscher⁴, Roosmarijn E Vandenbroucke^{2

3}, Christophe Van Steenkiste^{5

6}

Affiliations

¹ Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium.
² Barriers in Inflammation, VIB Center for Inflammation Research, Ghent, Belgium.
³ Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
⁴ Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences; Liver Research Center Ghent; Ghent University, Ghent, Belgium.
⁵ Antwerp University, Department of Gastroenterology and Hepatology, Antwerp, Belgium.
⁶ Department of Gastroenterology and Hepatology, Maria Middelares Hospital, Ghent, Belgium.

Abstract

Hepatic encephalopathy (HE) is a neurological complication of hepatic dysfunction and portosystemic shunting. It is highly prevalent in patients with cirrhosis and is associated with poor outcomes. New insights into the role of peripheral origins in HE have led to the development of innovative treatment strategies like faecal microbiota transplantation. However, this broadening of view has not been applied fully to perturbations in the central nervous system. The old paradigm that HE is the clinical manifestation of ammonia-induced astrocyte dysfunction and its secondary neuronal consequences requires updating. In this review, we will use the holistic concept of the neurogliovascular unit to describe central nervous system disturbances in HE, an approach that has proven instrumental in other neurological disorders. We will describe HE as a global dysfunction of the neurogliovascular unit, where blood flow and nutrient supply to the brain, as well as the function of the blood-brain barrier, are impaired. This leads to an accumulation of neurotoxic substances, chief among them ammonia and inflammatory mediators, causing dysfunction of astrocytes and microglia. Finally, glymphatic dysfunction impairs the clearance of these neurotoxins, further aggravating their effect on the brain. Taking a broader view of central nervous system alterations in liver disease could serve as the basis for further research into the specific brain pathophysiology of HE, as well as the development of therapeutic strategies specifically aimed at counteracting the often irreversible central nervous system damage seen in these patients.

Keywords: ABC, ATP-binding cassette; ACLF, acute-on-chronic liver failure; AD, acute decompensation; ALF, acute liver failure; AOM, azoxymethane; AQP4, aquaporin 4; Acute Liver Failure; Ammonia; BBB, blood-brain barrier; BCRP, breast cancer resistance protein; BDL, bile duct ligation; Blood-brain barrier; Brain edema; CCL, chemokine ligand; CCR, C-C chemokine receptor; CE, cerebral oedema; CLD, chronic liver disease; CLDN, claudin; CNS, central nervous system; CSF, cerebrospinal fluid; Cirrhosis; Energy metabolism; GS, glutamine synthetase; Glymphatic system; HE, hepatic encephalopathy; HO-1, heme oxygenase 1; IL-, interleukin; MMP-9, matrix metalloproteinase 9; MRP, multidrug resistance associated protein; NGVU; NGVU, neurogliovascular unit; NKCC1, Na-K-2Cl cotransporter 1; Neuroinflammation; OCLN, occludin; ONS, oxidative and nitrosative stress; Oxidative stress; P-gp, P-glycoprotein; PCA, portacaval anastomosis; PSS, portosystemic shunt; S1PR2, sphingosine-1-phosphate receptor 2; SUR1, sulfonylurea receptor 1; Systemic inflammation; TAA, thioacetamide; TGFβ, transforming growth factor beta; TJ, tight junction; TNF, tumour necrosis factor; TNFR1, tumour necrosis factor receptor 1; ZO, zonula occludens; mPT, mitochondrial pore transition.

Publication types

Review