Current status of novel antifibrotic therapies in patients with chronic liver disease

Abstract

Fibrosis accumulation is a dynamic process resulting from a wound-healing response to acute or chronic liver injury of all causes. The cascade starts with hepatocyte necrosis and apoptosis, which instigate inflammatory signaling by chemokines and cytokines, recruitment of immune cell populations, and activation of fibrogenic cells, culminating in the deposition of extracellular matrix. These key elements, along with pathways of transcriptional and epigenetic regulation, represent fertile therapeutic targets. New therapies include drugs specifically designed as antifibrotics, as well as drugs already available with well-established safety profiles, whose mechanism of action may also be antifibrotic. At the same time, the development of noninvasive fibrogenic markers, and techniques (e.g. fibroscan), as well as combined scoring systems incorporating serum and clinical features will allow improved assessment of therapy response. In aggregate, the advances in the elucidation of the biology of fibrosis, combined with improved technologies for assessment will provide a comprehensive framework for design of antifibrotics and their analysis in well-designed clinical trials. These efforts may ultimately yield success in halting the progression of, or reversing, liver fibrosis.

Keywords: cirrhosis; clinical trials; fibrosis; hepatic stellate cell; non-invasive fibrosis assessment.

Figure 1.

Schematic illustration of fibrosis progression. Hepatocyte damage and injury generate necrosis and apoptosis, which provoke cellular changes that stimulate the recruitment of inflammatory cells and activate fibrogenic cells. Different secreted signals from resident and recruited fibrogenic cells promote extracellular matrix synthesis. Repetitive bouts of injury trigger further progression to cirrhosis, whereas if injury subsides, then fibrosis regression may follow. Illustration courtesy of Alessandro Baliani, Copyright © 2011.

Figure 2.

The inflammatory cascade. The damaged hepatocyte releases apoptotic bodies which are engulfed by resident Kupffer cells and hepatic stellate cells (HSCs), which then promote HSC activation. Paracrine stimulation by reactive oxygen species, chemokines and cytokines also promote HSC activation. Chemokines either from the injured cells or activated HSCs also stimulate the recruitment of inflammatory cells that augment this cascade. Illustration courtesy of Alessandro Baliani, Copyright © 2011.

Figure 3.

Fibrosis versus resolution. As hepatic stellate cells (HSCs) activate and transdifferentiate to myofibroblasts, gene expression is altered, for example loss of peroxisome proliferator-activated receptor gamma (PPARγ) expression. Perpetuation involves distinct changes in HSC behavior that promote proliferation and contractility. In addition, paracrine stimulation, especially by platelet-derived growth factor (PDGF), increases the recruitment of myofibroblasts. Paracrine and endocrine signaling drive extracellular matrix (ECM) synthesis. Reducing the cause of injury may promote clearance of activated HSCs by apoptosis, senescence or reversion to quiescence. In addition, matrix degradation is augmented by increasing matrix metalloproteinase (MMP) activity and decreasing tissue inhibitor of metalloproteinase (TIMP). Illustration courtesy of Alessandro Baliani, Copyright © 2011.