New treatment options for liver fibrosis. From bench to bedside

Liver fibrosis, i.e., excessive hepatic scarring, is a common result of chronic liver diseases and may progress to cirrhosis. Rapidly increasing knowledge on the pathomechanisms of liver inflammation and fibrosis have prompted novel antifibrotic treatment strategies. Promising approaches include the modulation of cell death or inflammatory signaling pathways. Moreover, inhibiting the recruitment inflammatory immune cells into the liver, e.g., via the chemokine receptor CCR2 antagonist cenicriviroc, or inhibiting the inflammatory activation of macrophages, e.g., via galectin-3 inhibitors, are currently being evaluated in preclinical and early clinical studies. Likewise, novel antibodies against LOXL2 (simtuzumab) directly target the extracellular matrix, which is mainly composed of collagen and is stabilized by cross-links. The synthetic bile acid derivate obeticholic acid showed promising results in a phase 2 study (FLINT trial) in patients with nonalcoholic steatohepatitis (NASH) and fibrosis, prompting a multicenter phase III trial with this drug. The gut-liver axis is of exceptional relevance for fibrosis progression, and its components including gut microbiota, intestinal barrier function, and scavenger role of the liver for intestinal endotoxins represent additional targets for therapeutic interventions. Although the rapid knowledge transfer from bench to bedside is impressive, many aspects such as application schedule, patient selection, and appropriate end-points are not conclusively defined. Final results from ongoing trials need to be awaited regarding the efficacy of the new antifibrotic therapies.