Vicente Felipo
Several million patients with liver cirrhosis suffer Minimal Hepatic Encephalopathy (MHE), with psychomotor slowing and mild cognitive and coordination impairments that increase accidents, falls and hospitalizations and reduce their quality of life and life span. MHE is an important clinical, social and economic problem. Hyperammonemia and peripheral inflammation act synergistically to induce these neurological alterations. We have identified some alterations of the immune system associated with appearance of the neurological alterations in cirrhotic patients: Increased activation of all subtypes of CD4+ T-lymphocytes and of its differentiation to Th follicular and Th22. Patients died in HE show neuro-inflammation in cerebellum, with activation of microglia and astrocytes and loss of Purkinje cells. We study in animal models the mechanisms by which inflammation leads to neuro-inflammation; how neuro-inflammation alters neurotransmission and how this leads to cognitive and motor alterations. We identify therapeutic targets and assess whether treatments acting on these targets improve cognitive and motor function in rats with MHE. Rats with MHE show neuro-inflammation in hippocampus, with microglia and astrocytes activation and increased IL-1b and TNFa. This is associated with altered membrane expression of NMDA and AMPA receptors which, in turn, impairs spatial learning and memory. Rats with MHE also show neuro-inflammation in cerebellum, associated with altered GABA transporters and extracellular GABA which impair motor coordination and learning in a Y Maze. These alterations may be reversed by treatments that reduce peripheral inflammation: Anti-TNFa, reduce neuroinflammation: Sulforaphane, increase extracellular cGMP. The mechanisms by which inflammation induces neuro-inflammation, how this impairs neurotransmission and leads to cognitive and motor alteration would have common components in different pathologies including chronic diseases associated with inflammation, ageing and some mental and neurodegenerative diseases. Treatments useful to improve these mechanisms in MHE may be also useful in these pathologies. Current evidence suggests that chronic inflammatory dis
eases lead to neuroinflammation. Increased neuroinflamamtion can result in neurological impairment with deficits in cognition and motor function. For example, patients with diabetes, rheumatoid arthritis, obesity or chronic kidney disease can develop neurological deficits. Inflammation and neuroinflammation are major contributing factors to cognitive and motor deficits in situations such as postoperative cognitive dysfunction, ageing and in some mental (e.g. schizophrenia) and neurodegenerative (e.g. Alzheimer’s disease) diseases. Patients suffering from chronic liver diseases (mainly cirrhosisand/orhepatitis) also show chronic inflammation which can led to hepatic encephalopathy (HE): any alteration in cerebral function which is a consequence of previous liver failure. There are two main types of liver diseases which induce HE: acute liver failure and chronic liver diseases. The effects and mechanisms underlying the cerebral alterations in acute and chronic liver failure are completely different. This review will focus only on the mechanisms involved in HE in chronic liver diseases, mainly in liver cirrhosis