The neurogliovascular unit in hepatic encephalopathy - PubMed (original) (raw)

Review

The neurogliovascular unit in hepatic encephalopathy

Wouter Claeys et al. JHEP Rep. 2021.

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.

© 2021 The Authors.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

Fig. 1

Fig. 1

The neurogliovascular unit in hepatic encephalopathy. In patients with decompensated cirrhosis, circulating levels of cytokines, ammonia and bile acids are elevated and reach the brain. In patients with hepatic encephalopathy, cerebral blood flow and nutrient supply are impaired. The BBB becomes leaky, allowing toxins like ammonia to enter the brain. Ammonia induces astrocyte swelling and oxidative stress, impairing normal functioning and eventually resulting in brain oedema. Microglia are activated and produce inflammatory mediators, resulting in a neuroinflammatory environment, further aggravating neurogliovascular dysfunction. Finally, impaired glymphatic clearance results in the accumulation of neurotoxic compounds. BBB, blood-brain barrier; Gln, glutamine; NH3, ammonia; ROS, reactive oxygen species.

Fig. 2

Fig. 2

Energy metabolism is impaired. (A) In hepatic encephalopathy, vascular resistance is increased in the cerebral circulation, leading to decreased blood flow and thus supply of oxygen and nutrients to the brain. (B) Additionally, ammonia inhibits key Krebs cycle enzymes like alpha-ketoglutarate dehydrogenase, leading to ATP depletion. (C) Inflammation leads to preferential energy and nutrient allocation towards the innate immune system. Ketone body production by the cirrhotic liver as an alternative energy source for the brain is insufficient. Additionally, toxic compounds like kynurenines and GABA precursors accumulate secondary to increased amino acid metabolism. Lactate, the end product of glycolysis, accumulates in the brain and might act as an osmolyte, leading to astrocyte swelling and brain oedema. GABA, gamma amino butyric acid; NH3, ammonia.

Fig. 3

Fig. 3

Blood-brain barrier structure and function is altered in hepatic encephalopathy. (A) In (chronic) liver disease, levels of circulating ammonia, bile acids, cytokines, MMP-9 and TGFβ1 are increased. MMP-9 degrades TJ proteins like occludin and claudin-5. TGFβ1 leads to additional MMP-9 production by cerebral endothelial cells. Bile acids lead to deficient formation of TJs. Finally, cytokines like TNF decrease expression of TJ proteins like occludin. TJ breakdown leads to indiscriminate influx of toxins like ammonia. (B) Efflux transporters like BCRP protect the brain from drugs and other xenobiotics. Ammonia and bilirubin, which accumulate in conditions of HE, reduce expression and functionality of BCRP. This increases brain concentrations of xenobiotics and other ligands of BCRP and makes patients more susceptible to these compounds. BBB, blood-brain barrier; BCRP, breast cancer resistance protein; HE, hepatic encephalopathy; MMP-9, matrix metalloproteinase 9; NH3, ammonia; TGFβ, transforming growth factor beta; TJ, tight junction; TNF, tumour necrosis factor.

Fig. 4

Fig. 4

Astrocytes swell and are subject to oxidative stress in hepatic encephalopathy. (A) Ammonia is metabolised into glutamine by glutamine synthetase. Glutamine acts as an osmolyte. Alternatively, glutamine is shuttled into the mitochondria, leading to mitochondrial pore transition and oxidative stress. Both mechanisms contribute to astrocyte swelling and cerebral oedema. (B) Astrocyte exposure to excess ammonia leads to overactivation of NKCC1 and the SUR1-regulated NCCa-ATP channel, resulting in influx of ions into the cell. Water follows the gradient created through increased AQP4 water channels, finally resulting in astrocyte swelling and cerebral oedema. (C) Ammonia leads to Ca2+ influx, activation of NADPH oxidase and mitochondrial pore transition. Tryptophan metabolites might also induce free radical production. These mechanisms increase levels of ROS, which enters a positive feedback loop with astrocyte swelling. Additionally, it leads to astrocyte senescence, possibly explaining the irreversible symptoms of HE. AQP4, aquaporin 4; Gln, glutamine; HE, hepatic encephalopathy; NADPH, nicotinamide adenine dinucleotide phosphate; NH3, ammonia; NKCC1, Na-K-2Cl cotransporter 1; ROS, reactive oxygen species; SUR1, sulfonylurea receptor 1.

Fig. 5

Fig. 5

Mechanisms and consequences of microglial activation in hepatic encephalopathy. In (chronic) liver disease, circulating levels of ammonia, TCA, TGFβ1 and cytokines like TNF are increased. TGFβ1, TNF and TCA bind to their respective neuronal receptors, which respond with CCL2 production. CCL2 binds to CCR2/4 on microglia, resulting in an activated phenotype. Additionally, hyperammonaemia can induce peripheral TNF increases, which induces microglial activation through the TNFR1, although whether this effect is direct or indirect is not known. Whether compounds like bile acids and cytokines have a direct influence on microglia in HE is unknown. The direct effect of hyperammonaemia on microglia is still an open question. Microglial activation results in cytokine production and recruitment of peripheral immune cells, in particular monocytes. This constitutes a neuroinflammatory environment, which is detrimental to brain functioning. CCL, chemokine ligand; CCR, C-C chemokine receptor; NH3, ammonia; TCA, taurocholic acid; TGFβ, transforming growth factor beta; TNF, tumour necrosis factor; TNFR1, TNF receptor 1.

Fig. 6

Fig. 6

Glymphatic dysfunction leads to accumulation of toxins and neuroinflammation. In chronic liver disease, AQP4 vessel coverage is decreased. This impairs the flow of solutes and toxins from the periarterial to the perivenous space and further on to meningeal lymphatic vessels. Subsequently, these compounds accumulate in the brain parenchyma, activating microglia and promoting a neuroinflammatory microenvironment, which disturbs normal brain functioning. AQP4, aquaporin 4; HE, hepatic encephalopathy.

Similar articles

Cited by

References

    1. Bustamante J., Rimola A., Ventura P.-J., Navasa M., Cirera I., Reggiardo V. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999 May;30(5):890–895. - PubMed
    1. Vilstrup H., Amodio P., Bajaj J., Cordoba J., Ferenci P., Mullen K.D. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European association for the study of the liver and the American association for the study of liver diseases. J Hepatol. 2014 Sep;61(3):642–659. - PubMed
    1. Lopez-Franco O., Morin J., Cortes-Sol A., Molina-Jimenez T., Del Moral D.I., Flores-Munoz M. Cognitive impairment after resolution of hepatic encephalopathy: a systematic review and meta-analysis. Front Neurosci. 2021;15:11. - PMC - PubMed
    1. Ochoa-Sanchez R., Tamnanloo F., Rose C.F. Hepatic encephalopathy: from metabolic to neurodegenerative. Neurochem Res. 2021 Jun 15 doi: 10.1007/s11064-021-03372-4. - DOI - PubMed
    1. Tapper E.B., Jiang Z.G., Patwardhan V.R. Refining the ammonia hypothesis. Mayo Clin Proc. 2015 May;90(5):646–658. - PubMed

Publication types

LinkOut - more resources