Grant: Project Grant

The number of patients developing chronic liver disease/cirrhosis has risen more than 50% in the last 20 years. Unfortunately, chronic liver disease leads to complications including hepatic encephalopathy (HE), which touches close to 80% of patients. The burden of HE is immense considering its wide-ranging effects on patients, families and society. Severe/overt HE (OHE) is the primary reason for hospitalizations. Intriguingly, it has been reported that patients who experience multiple episodes of OHE become very difficult to treat. Indeed, even following liver transplantation, which should lead to normalization, encephalopathy still persists in close to 50% of patients. This suggests that repeated episodes of OHE may be causing permanent damage and irreversibility. Ammonia and infection are believed to be major factors involved in the pathogenesis of HE. Hyperammonemia, due to liver disease, leads to neurotoxic levels of ammonia and in addition, patients with cirrhosis are prone to infection (severe inflammation). Even though both hyperammonemia and inflammation cause OHE, it is unclear whether these factors cause the same "type" of OHE and therefore impact brain function differently. In our proposal, we intend to unravel and understand the role of each of these distinct pathogenic factors in causing OHE and irreversibility. Remarkably, the presence or increase in these factors does not always trigger OHE and the status of the brain will dictate its susceptibility to OHE. Therefore, we will investigate the role of subclinical/minimal HE (diagnosed using neuropsychological tests) on the susceptibility to these factors as well as discover biomarkers which will allow identifying patients with cirrhosis who are at risk of developing OHE. Finally, understanding the pathophysiological mechanisms that lead to episodic and irreversible HE as well as identifying tools and biomarkers to enable to predict OHE during liver disease are the overarching aims of the proposal.