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The liver–brain axis in liver failure: neuroinflammation and encephalopathy

Nature Reviews Gastroenterology & Hepatology volume 10, pages 522–528 (2013)Cite this article

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Abstract

Systemic inflammation is common in liver failure and its acquisition is a predictor of hepatic encephalopathy severity. New studies provide convincing evidence for a role of neuroinflammation (inflammation of the brain per se) in liver failure; this evidence includes activation of microglia, together with increased synthesis in situ of the proinflammatory cytokines TNF, IL-1β and IL-6. Liver–brain signalling mechanisms in liver failure include: direct effects of systemic proinflammatory molecules, recruitment of monocytes after microglial activation, brain accumulation of ammonia, lactate and manganese, and altered permeability of the blood–brain barrier. Ammonia and cytokines might act synergistically. Existing strategies to reduce ammonia levels (including lactulose, rifaximin and probiotics) have the potential to dampen systemic inflammation, as does albumin dialysis, mild hypothermia and N-acetylcysteine, the latter two agents acting at both peripheral and central sites. Minocycline, an agent with potent central anti-inflammatory properties, reduces neuroinflammation, brain oedema and encephalopathy in liver failure, as does the anti-TNF agent etanercept.

Key Points

  • Both acute and chronic liver failure result in neuroinflammation—an inflammatory response in the central nervous system (CNS) characterized by microglial activation and brain accumulation of proinflammatory cytokines

  • Evidence suggests that neuroinflammation contributes to the pathogenesis of the CNS manifestations of acute and chronic liver failure, including hepatic encephalopathy as well as brain oedema and its complications

  • Liver-to-brain proinflammatory signalling in liver failure involves humoral and neural routes; new evidence indicates that monocyte recruitment, changes in levels of ammonia, lactate, manganese and alterations in blood–brain barrier permeability might also have a key role

  • Many currently available therapies used in the treatment of encephalopathy and brain oedema in liver failure (including lactulose, albumin dialysis and mild hypothermia) have the requisite properties to limit systemic and/or neuroinflammation

  • Early investigations found that anti-inflammatory agents (such as ibuprofen, anti-TNF agents and minocycline) are effective in the treatment of the CNS complications of experimental liver failure

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Figure 1: Underlying mechanisms of hepatic encepthalopathy.
Figure 2: Microglial activation in the brains of rats with ALF.
Figure 3: Microglial activation in a patient with cirrhosis and mild hepatic encephalopathy imaged using PET and the translocator protein ligand 11C-PK11195.

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R. F. Butterworth has served as consultant and benefited from financial support as a speaker at conferences in an ad hoc manner from the following pharmaceutical companies: Merz Pharmaceuticals, Otsuka Pharmaceuticals and Salix Pharmaceuticals. The author and his family have no direct financial interests in any of these companies.

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Butterworth, R. The liver–brain axis in liver failure: neuroinflammation and encephalopathy. Nat Rev Gastroenterol Hepatol 10, 522–528 (2013). https://doi.org/10.1038/nrgastro.2013.99

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