Hepatic encephalopathy: effects of liver failure on brain function

Journal name:
Nature Reviews Neuroscience
Volume:
14,
Pages:
851–858
Year published:
DOI:
doi:10.1038/nrn3587
Published online

Abstract

Liver failure affects brain function, leading to neurological and psychiatric alterations; such alterations are referred to as hepatic encephalopathy (HE). Early diagnosis of minimal HE reveals an unexpectedly high incidence of mild cognitive impairment and psychomotor slowing in patients with liver cirrhosis — conditions that have serious health, social and economic consequences. The mechanisms responsible for the neurological alterations in HE are beginning to emerge. New therapeutic strategies acting on specific targets in the brain (phosphodiesterase 5, type A GABA receptors, cyclooxygenase and mitogen-activated protein kinase p38) have been shown to restore cognitive and motor function in animal models of chronic HE, and NMDA receptor antagonists have been shown to increase survival in acute liver failure. This article reviews the latest studies aimed at understanding how liver failure affects brain function and potential ways to ameliorate these effects.

At a glance

Figures

  1. Progression of alterations in the frontal cortex and cerebellum during acute liver failure in rats.
    Figure 1: Progression of alterations in the frontal cortex and cerebellum during acute liver failure in rats.

    Acute liver failure (ALF) affects different brain areas in different ways. At early stages of ALF there is no effect on blood–brain barrier (BBB) permeability or oedema in the frontal cortex, whereas the cerebellum shows increased BBB permeability and vasogenic oedema. Blood flow and lactate are not affected at early stages of ALF, but at later stages (grades 3 and 4 of hepatic encephalopathy), the cerebellum shows increased lactate and reduced blood flow. By contrast, the frontal cortex shows cytotoxic oedema and increased blood flow12.

  2. Motor alterations in MHE.
    Figure 2: Motor alterations in MHE.

    a | Motor activation induced by activation of metabotropic glutamate receptors (mGluRs) in the nucleus accumbens (NAc) is mediated by different mechanisms and neuronal circuits in rats with hepatic encephalopathy (HE) and in control rats31. In control rats, activation of mGluRs by 3,5-dihydroxyphenylglycine (DHPG) in the NAc induces the release of dopamine (DA), which elicits locomotion by activating the circuit that connects the NAc to the cortex (medial prefrontal cortex (mPFC)) through the ventral pallidum (VP) and the mediodorsal thalamus (MDT). However, in rats with minimal HE (MHE), activation of mGluRs by DHPG in the NAc induces a release of glutamate, which elicits locomotion by activating the alternative circuit that connects the NAc to the mPFC via the substantia nigra pars reticulata (SNr) and the ventromedial thalamus (VMT). b | Under normal conditions, in the absence of activation of mGluRs in the NAc, rats with MHE show hypokinesia. In these rats, neuroinflammation reduces the amount and function of glutamate transporters in the SNr and increases extracellular glutamate levels and activation of mGluR1; this alters the function of the motor circuit between the basal ganglia, the thalamus and the cortex, leading to increased levels of extracellular GABA in the VMT, which reduces extracellular glutamate levels in the primary motor cortex (pMC) and leads to hypokinesia32. Blocking mGluR1 stereotaxically in the SNr with an antagonist (CPCCOEt) restores normal function of the neuronal circuit and motor activity32. Treatment with ibuprofen restores the amount of glutamate transporters and reduces the levels of extracellular glutamate in the SNr, and also restores motor activity17. The circuits shown in part a have been modified, with permission, from Ref. 34 © (2007) John Wiley and Sons.

  3. Cognitive impairment in MHE.
    Figure 3: Cognitive impairment in MHE.

    Chronic hyperammonaemia reduces the function of the glutamate–nitric oxide (NO)–cyclic GMP pathway. Chronic hyperammonaemia enhances tonic activation of NMDA and type A GABA (GABAA) receptors, leading to increased activity of calcium/calmodulin-dependent protein kinase II (CaMKII), which phosphorylates (P) neuronal NO synthase (NOS) on Ser847, reducing its activity and NO formation. This results in lower activation of soluble guanylyl cyclase (sGC) and reduced synthesis of cGMP, which in rats leads to reduced learn ability in a Y maze task. Neuroinflammation also impairs the function of the glutamate–NO–cGMP pathway in the cerebellum, leading to reduced learning ability. Hyperammonaemia induces neuroinflammation, but other factors associated with liver failure could also contribute to neuroinflammation. CM, calmodulin.

  4. Targets and agents that could improve cognitive function in patients with MHE.
    Figure 4: Targets and agents that could improve cognitive function in patients with MHE.

    Compounds that restore the function of the glutamate (Glu)–nitric oxide (NO)–cyclic GMP pathway and cGMP levels restore learning ability in rats. This may be achieved with phosphodiesterase 5 (PDE5) inhibitors, anti-inflammatory drugs, p38 inhibitors or modulators of type A GABA receptors (GABAARs). Although ibuprofen may affect kidney function in patients with cirrhosis, PDE5 inhibitors are being used in patients with cirrhosis and minimal hepatic encephalopathy (MHE) to treat erectile dysfunction without secondary effects. Thus, they may be useful to improve cognitive function in these patients. p38 inhibitors are still under development but, when available, may also be useful in the treatment of MHE. Modulators of GABAARs should be carefully tested to avoid secondary effects, but modulators such as some neurosteroids could improve cognitive function in patients with MHE. CaMKII, calcium/calmodulin-dependent protein kinase II; CM, calmodulin; NMDAR, NMDA receptor; NOS, NO synthase; sGC, soluble guanylyl cyclase.

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Affiliations

  1. Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera 3, 46012 Valencia, Spain.

    • Vicente Felipo

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The author declares no competing interests.

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Author details

  • Vicente Felipo

    Vicente Felipo obtained a Ph.D. in biochemistry from Valencia University, Spain, in 1983. He has led the Laboratory of Neurobiology of the CIPF (Centro de Investigación Príncipe Felipe, Valencia, Spain) since its establishment in 1990 and the CIPF Program on Neurological Impairment since it was established in 2012. His research focuses on basic and translational research on cognitive, motor, sleep- and circadian-rhythm alterations in different pathological situations, including: minimal and clinical hepatic encephalopathy, hyperammonaemia and developmental exposure to food and environmental contaminants.
    Vicente Felipo's homepage.

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