Grant: Project Grant

Hepatic encephalopathy (HE), characterized by cognitive, psychiatric and motor disturbances, is a devastating complication of liver disease. With as much as 80% of patients with cirrhosis suffering from HE, the burden of HE is immense considering its wide-ranging effects on the patients, family and society. Ammonia is believed to be the major factor involved in the pathogenesis of HE. Cirrhosis causes an increase in blood ammonia (hyperammonemia) which leads to increased neurotoxic levels of ammonia in the brain. Obesity has become a major worldwide health problem. As a result, the number of patients with liver disease due to fatty-liver is rising and is becoming the leading cause of cirrhosis. Obesity has been demonstrated to induce cognitive changes but it is not clear how obesity impact HE. Our project proposes to study the effect of ammonia and obesity alone as well as together on neurological dysfunction. This will be studied using complimentary rat models of cirrhosis and obesity and closely looking at the impact of fatty acids, adipokines and ammonia on the blood-brain barrier. In addition, lipids can infiltrate into muscle (myosteatosis) which can impact the muscle's capacity to remove ammonia. Therefore, obesity can directly (via the blood brain barrier) or indirectly (by inhibiting ammonia clearance in the muscle) affect the brain, leading to a higher risk of developing HE. Cognitive impairment due to obese cirrhosis will be a challenging population of patients to treat as neurological dysfunction may develop due to either hyperammonemia and/or obesity. To date, treatment strategies remain an unmet clinical need in this population of patients. Therefore, the results from this project will provide valuable insights on the pathogenesis of cognitive impairment in patients with obesity-induced cirrhosis and lead to new management strategies for these patients.