Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts

Abstract

Hepatic fibrosis is characterized by the formation and deposition of excess fibrous connective tissue, leading to progressive architectural tissue remodeling. Irrespective of the underlying noxious trigger, tissue damage induces an inflammatory response involving the local vascular system and the immune system and a systemic mobilization of endocrine and neurological mediators, ultimately leading to the activation of matrix-producing cell populations. Genetic disorders, chronic viral infection, alcohol abuse, autoimmune attacks, metabolic disorders, cholestasis, alterations in bile acid composition or concentration, venous obstruction, and parasite infections are well-established factors that predispose one to hepatic fibrosis. In addition, excess fat and other lipotoxic mediators provoking endoplasmic reticulum stress, alteration of mitochondrial function, oxidative stress, and modifications in the microbiota are associated with non-alcoholic fatty liver disease and, subsequently, the initiation and progression of hepatic fibrosis. Multidisciplinary panels of experts have developed practice guidelines, including recommendations of preferred therapeutic approaches to a specific cause of hepatic disease, stage of fibrosis, or occurring co-morbidities associated with ongoing loss of hepatic function. Here, we summarize the factors leading to liver fibrosis and the current concepts in anti-fibrotic therapies.

Protein Abundance of Hepatic Drug Transporters in Patients With Different Forms of Liver Damage

“…In this study, and in other published reports, dissected samples from cirrhotic livers were analyzed, which could have an impact on the reported results. Progression of liver dysfunction is associated with reduction in a number of hepatocytes, while other components of liver structure may expand (depending on liver pathology type and disease stage), i.e., nonparenchymal cells (sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells), cellular components of the extracellular space (fibroblasts and transdifferentiated myofibroblasts) and fibrous connective tissue . The fraction of functional liver mass in Child‐Pugh class A, B, and C was shown to be 69%, 55%, and 28%, respectively, as compared with the control samples .…”

Therapeutic Targeting of Hepatic Macrophages

“…As mentioned earlier, hepatic macrophages interact with HSCs, whereby, upon activation, HSCs undergo functional and morphological changes resulting in proliferative myofibroblasts that produce excessive ECM and secrete numerous pro-inflammatory and pro-fibrotic factors [12,24]. Since it is known that these events promote inflammation and contribute to liver fibrogenesis, HSCs are considered to be the main effector cells in hepatic fibrosis [25].…”

Development of Capsular Fibrosis Beneath the Liver Surface in Humans and Mice

“…Steven Balog, 1 Yuchang Li, 1 Tomohiro Ogawa, 1,2 Toshio Miki, 3 Takeshi Saito, 1,4 Samuel W. French, 5 and Kinji Asahina 1 Glisson's capsule is the connective tissue present in the portal triad as well as beneath the liver surface. Little is known about how Glisson's capsule changes its structure in capsular fibrosis (CF), which is characterized by fibrogenesis beneath the liver surface.…”

“…Currently, no treatment cures patients with cirrhosis other than liver transplantation. (5) Although HSCs are recognized as a major source of myofibroblasts in LF, portal fibroblasts in the portal triad are known to participate in biliary fibrosis. (6)(7)(8) Glisson's capsule is the connective tissue that sheaths the portal vein, hepatic artery, and bile duct in the portal triad.…”

“…Myofibroblasts synthesize proinflammatory cytokines and extracellular matrix (ECM) proteins and participate in the progression to liver fibrosis (LF) and cirrhosis. Currently, no treatment cures patients with cirrhosis other than liver transplantation …”