The Inside-Out of End-Stage Liver Disease: Hepatocytes are the Keystone

Abstract

Chronic liver injury results in cirrhosis and end-stage liver disease (ESLD) which represents a leading cause of death worldwide, affecting people in their most productive years of life. Medical therapy can extend life, but the only definitive treatment is liver transplantation (LT). However, LT remains limited by access to quality donor organs and suboptimal long-term outcomes. The degeneration from healthy-functioning livers to cirrhosis and ESLD involves a dynamic process of hepatocyte damage, diminished hepatic function, and adaptation. However, the mechanisms responsible for deterioration of hepatocyte function and ultimately hepatic failure in man are poorly understood. We review the current understanding of cirrhosis and ESLD as a dynamic process and outline the current mechanisms associated with the development of hepatic failure from the clinical manifestations to energy adaptations, regeneration, and regulation of nuclear transcription factors. A new generation of therapeutics could target stabilization of hepatocyte differentiation and function to avoid the need for transplantation in patients with cirrhosis and ESLD.

Loss of liver function in chronic liver disease: An identity crisis

“…However, evidence accumulated over the past two decades indicates that breakdown of hepatic function cannot be simply ascribed to reduced parenchymal mass. Functional deficiencies of chronically injured and regenerating hepatocytes may underlie liver failure in cirrhosis, and these can be related to an impairment in the expression of genes that typify the mature hepatocyte phenotype [20,21]. Herein, after summarizing the current understanding of how hepatocellular differentiation occurs during development, we will discuss mechanisms leading to the loss of hepatocellular identity and organ dysfunction in chronic liver injury.…”

Human Hepatocellular response in Cholestatic Liver Diseases

“…These hepatocytes may therefore have different gene expression than what would be expected in early disease, as supported by published reports describing altered gene expression and immune dysfunction in advanced stages of liver disease. 19 , 28 , 29 Additionally, there may also be an association with paradoxical expression of these genes and advanced disease progression, which we may be inadvertently selecting due to our samples being exclusively from end-stage, transplant patients with PBC and PSC.…”

Contemporary Insights into Hepatitis C Virus: A Comprehensive Review

“…As cirrhosis advances, complications such as portal hypertension develop, and there is an escalated risk of HCC due to neoplastic transformations within the hepatic parenchyma [ 255 , 256 ]. Understanding this pathophysiological process that culminates in end-stage liver disease is necessary for timely and effective therapeutic interventions to halt or reverse the fibrosis processes in chronic HCV infection [ 257 , 258 ].…”