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Review Article

Neuroinflammation and neurological alterations

in chronic liver diseases

1
2
Carmina Montoliu , Marta Llansola , Vicente Felipo 2
1 Research Foundation of the Clinic Hospital of Valencia, Health Research Institute‑INCLIVA, 46010 Valencia, Spain.
2 Laboratory of Neurobiology, Prince Felipe Research Center, 46012 Valencia, Spain.

ABSTRA CT

Several million people with chronic liver diseases (cirrhosis, hepatitis) show neurological alterations, named hepatic
encephalopathy (HE) with cognitive and motor alterations that impair quality of life and reduces life span. Inflammation acts
synergistically with hyperammonemia to induce cognitive and motor alterations in patients with chronic liver disease and minimal
hepatic encephalopathy (MHE). Previous studies in animal models have suggested that neuroinflammation is a major player in HE.
This would also be the case in patients with liver cirrhosis or hepatitis C with HE. Rats with MHE show microglial activation and
neuroinflammation that is associated with cognitive impairment and hypokinesia. The anti‑inflammatory drug ibuprofen reduces
microglial activation and neuroinflammation and restores cognitive and motor functions in rats with MHE. Chronic hyperammonemia
per se induces neuroinflammation. Both peripheral inflammation and hyperammonemia would contribute to neuroinflammation in
chronic liver failure. Therefore, neuroinflammation may be a key therapeutic target to improve the cognitive and motor alterations in
MHE and overt HE. Identifying new targets to reduce neuroinflammation in MHE without inducing secondary effects would serve to
develop new therapeutic tools to reverse the cognitive and motor alterations in patients with HE associated with chronic liver diseases.

Key words: Cognitive impairment, hepatic encephalopathy, hyperammonemia, inflammation, motor function, neuroinflammation

INTRODUCTION of previous liver failure. [17] There are two main types
of liver diseases which induce HE: acute liver failure
Current evidence suggests that chronic inflammatory and chronic liver diseases. The effects and mechanisms
diseases lead to neuroinflammation. Increased underlying the cerebral alterations in acute and chronic
neuroinflamamtion can result in neurological impairment liver failure are completely different. [17] This review
with deficits in cognition and motor function. For example, will focus only on the mechanisms involved in HE in
patients with diabetes, rheumatoid arthritis, obesity chronic liver diseases, mainly in liver cirrhosis.
or chronic kidney disease can develop neurological
deficits. [1-9] Inflammation and neuroinflammation are Chronic liver diseases affect more than 5 million
major contributing factors to cognitive and motor deficits people in USA and a similar number in the European
in situations such as postoperative cognitive dysfunction, Union. [18] Patients with the chronic liver disease do not
ageing and in some mental (e.g. schizophrenia) show neurological alterations at the beginning of the
and neurodegenerative (e.g. Alzheimer’s disease) disease. However, with the progression of liver failure,
diseases. [10-16] most of these patients will suffer from some grade of
HE. There are two main forms of HE in chronic liver
Patients suffering from chronic liver diseases (mainly disease: (1) minimal hepatic encephalopathy (MHE),
cirrhosis and/or hepatitis) also show chronic inflammation in which the symptoms are not evident but can be
which can led to hepatic encephalopathy (HE): any unveiled using psychometric tests and (2) clinical or
alteration in cerebral function which is a consequence overt HE, in which the symptoms are evident. Once
the symptoms are evident, clinical HE is graded in four
Access this article online [19]
stages according to the West Haven criteria.
Quick Response Code:
Website: Approximately, 40-50% of cirrhotic patients present
www.nnjournal.net
with MHE with mild cognitive impairment, attention
DOI: deficits, psychomotor slowing, reduced mental
10.4103/2347-8659.160845 processing speed and bimanual and visuomotor
incoordination. [20-22] This incidence means that more

Corresponding Author: Dr. Vicente Felipo, Laboratory of Neurobiology, Prince Felipe Research Center, Calle Eduardo Primo
Yufera, 3, 46012 Valencia, Spain. E‑mail: vfelipo@cipf.es

138 Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015