Katherine McKay

Title: Mechanistic Basis of Cognitive Impairment in Cholestatic Liver Disease

Summary: Primary Biliary Cirrhosis (PBC) is a chronic liver disease in which autoimmune damage of bile ducts causes impaired flow of bile. Toxic bile acids cause progressive damage to the bile ducts and liver. Eventually, patients suffer liver failure potentially requiring transplant. Patients experience itch and fatigue as well as cognitive symptoms, including memory and concentration problems, which are significant and debilitating. The mechanisms behind these cognitive symptoms have not been elucidated, nor have any effective treatments been identified.

Progress is being made in treatments of PBC, with therapeutic compounds currently under trial. Unpublished work from the lab showed that mice which have undergone bile duct ligation (BDL) surgery show problems with cognition similar to PBC patients. Prophylactic treatment with one of these compounds significantly improved symptoms compared to untreated BDL mice.

We are examining samples from these mice to uncover the mechanism behind the symptoms. We are assessing liver, blood and brain to investigate whether there are changes in inflammation and working to establish whether there is a change in the bile composition and the impact on other tissues, in particular whether certain bile acids cause damage to or protect brain tissue. The work so far suggests that a change in inflammation is not the driving factor.

In addition, a study is being organised to assess patients with PBC. The aim of this is to characterise in detail patients with and without cognitive impairment such that a trial of new compounds can have useful outcomes to measure the effectiveness of any potential drug. The hope is that combining these two approaches could lead to more effective treatments for patients.