Prediction and Prevention of Hepatic Decompensation in Patients with Cirrhosis

ASTRACT
Liver cirrhosis and its complications cause significant morbidity and mortality in the United States. Cirrhosis and
cirrhosis-related mortality are rising in parallel with shifts in the demographics driven by increases in alcoholic-
and nonalcoholic- fatty liver disease. Current cirrhotic populations are enriched with older patients with damage
in other tissues caused by obesity, the metabolic syndrome, and/or alcohol. These factors confound cirrhosis
management and often preclude liver transplantation as a therapeutic option. Consequently, the number of
patients with decompensated cirrhosis is growing. Hepatic decompensation results from loss of functional liver
parenchyma and the severity of liver dysfunction is a proven-predictor of cirrhosis-related morbidity and mortality.
Therefore, our overall objective is to develop novel approaches to preserve liver function and prevent hepatic
decompensation in cirrhosis. Success necessitates more information about: i) modifiable risks that drive hepatic
dysfunction and ii) how hepatic dysfunction impacts the health of other organs. To address these gaps in
knowledge, we will conduct a longitudinal cohort study of patients with cirrhosis (Aim 1) and develop/implement
an interventional trial using an HMG CoA reductase inhibitor (statin) in cirrhotic patients who are at high risk for
hepatic decompensation. Both aims are grounded by the scientific premise that cirrhosis is caused by defective,
maladaptive liver regeneration. Our pre-clinical research: i) reveals that liver regeneration requires tightly scripted
reactivation of developmental signaling pathways that were once thought to be silenced in adult livers (but known
to reactivate in cancer) and ii) shows that when these pathways become dysregulated, they impair regeneration
and drive liver disease to progress to cirrhosis and cancer. These findings explain why organ failure, fibrosis
and cancer risk typically evolve in parallel and justify research in human cirrhotic populations to identify factors
that impact the regenerative mechanisms (Aim1). They also provide a strong conceptual basis for evaluating
the ability of statins to improve liver function in cirrhosis (Aim2) because statins have anti-inflammatory and
metabolic actions that are predicted to favorably modulate regenerative pathways. The Duke Liver Program is
ideally-positioned for membership in the new Cirrhosis Clinical Network which will be configured to accomplish
these aims: our multidisciplinary team of providers cares for a large, diverse cirrhotic population and we have
had strong institutional support to develop outstanding programs in liver disease research and personalized
medicine. Successful accomplishment of our Aims will enable a more ‘personalized’ approach to management
that will improve cirrhosis outcomes despite challenging co-morbid conditions.