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“Let my liver rather heat with wine” - a review of hepatic fibrosis pathophysiology and emerging therapeutics

Authors Moscoso CG, Steer CJ

Received 25 April 2019

Accepted for publication 17 August 2019

Published 2 September 2019 Volume 2019:11 Pages 109—129


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Gerry Lake-Bakaar

Carlos G Moscoso,1 Clifford J Steer1,2

1Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition; 2Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA

Correspondence: Carlos G Moscoso; Clifford J Steer
Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, Phillips-Wangensteen Building, 516 Delaware Street, S.E., Minneapolis, MN 55455, USA
Tel +1 612 625 8999
Fax +1 612 625 5620

Abstract: Cirrhosis is characterized by extensive hepatic fibrosis, and it is the 14th leading cause of death worldwide. Numerous contributing conditions have been implicated in its development, including infectious etiologies, medication overdose or adverse effects, ingestible toxins, autoimmunity, hemochromatosis, Wilson’s disease and primary biliary cholangitis to list a few. It is associated with portal hypertension and its stigmata (varices, ascites, hepatic encephalopathy, combined coagulopathy and thrombophilia), and it is a major risk factor for hepatocellular carcinoma. Currently, orthotopic liver transplantation has been the only curative modality to treat cirrhosis, and the scarcity of donors results in many people waiting years for a transplant. Identification of novel targets for pharmacologic therapy through elucidation of key mechanistic components to induce fibrosis reversal is the subject of intense research. Development of robust models of hepatic fibrosis to faithfully characterize the interplay between activated hepatic stellate cells (the principal fibrogenic contributor to fibrosis initiation and perpetuation), hepatocytes and extracellular matrix components has the potential to identify critical components and mechanisms that can be exploited for targeted treatment. In this review, we will highlight key cellular pathways involved in the pathophysiology of fibrosis from extracellular ligands, effectors and receptors, to nuclear receptors, epigenetic mechanisms, energy homeostasis and cytokines. Further, molecular pathways of hepatic stellate cell deactivation are discussed, including apoptosis, senescence and reversal or transdifferentiation to an inactivated state resembling quiescence. Lastly, clinical evidence of fibrosis reversal induced by biologics and small molecules is summarized, current compounds under clinical trials are described and efforts for treatment of hepatic fibrosis with mesenchymal stem cells are highlighted. An enhanced understanding of the rich tapestry of cellular processes identified in the initiation, perpetuation and resolution of hepatic fibrosis, driven principally through phenotypic switching of hepatic stellate cells, should lead to a breakthrough in potential therapeutic modalities.

Keywords: fibrosis, cirrhosis, hepatic stellate cell, reversal, transdifferentiation, senescence, apoptosis

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