Hepatic encephalopathy (HE) is one of the most common manifestations of decompensated cirrhosis. Approximately 70% of patients with cirrhosis also have subacute hepatic encephalopathy (SHE), as demonstrated on neuropsychological testing. The use of transjugular intrahepatic portosystemic shunts (TIPS), which acts as a side-to-side shunt, has become common to manage complications of cirrhosis. However, TIPS are associated with adverse effects, including worsening of existing HE or the precipitation of overt HE and liver failure. Liver transplantation has become the ideal management for patients who have decompensated liver disease. The principal hypothesis of this proposal is that changes of HE and SHE can be determined by neuropsychological testing and changes in cerebral blood flow (CBF). The Specific Aims are the following: (1) Determine the changes in cognitive function in patients with cirrhosis; (2) Identify changes in CBF and neurotransmitter activity, as assessed by central benzodiazepine receptor binding and serotonin transporter binding after TIPS insertion; (3) Identify changes in CBF and neurotransmitter activity, as assessed by central benzodiazepine receptor binding and serotonin transporter binding after liver transplantation; and (4) Correlate the neuropsychological changes with cognitive function and central benzodiazepine receptor binding and serotonin transporter binding. These Specific Aims will be pursued in 60 subjects: group I will be 20 cirrhotics who will undergo TIPS; group II will be 20 cirrhotic patients who are scheduled to undergo liver transplantation; and group III will be 20 age and sex matched cirrhotic controls. All groups will be studied with a battery of neuropsychological tests and stimulated CBF, using 1502 labeled water, while half of groups I and II will be tested with 11C flumazenil PET or (11C)(+)McN5652 positron emission tomography (PET), in order to determine central benzodiazepine receptor binding and serotonin transporter binding, respectively, before and one month after undergoing TIPS or liver transplantation. The control group will be studied with 11C flumazenil PET or (11C)(+)McN5652 PET at baseline and 1 month, thereafter. In aggregate, these studies will provide a platform to elucidate cognitive and biological mechanisms underlying hepatic encephalopathy with the ultimate goal of enhancing diagnosis and management. Additionally, the proposed studies will be guided by a team of mentors and sponsors and supplemented by a didactic curriculum, all to lay the foundation for eventual independent clinical investigator status.
NIH ExPorter
NIH ExPorter