Advances in understanding of the pathophysiologic basis of fibrogenesis are now leading to novel therapeutic approaches. Cure of the primary disease to prevent ongoing injury remains the most effective strategy to reverse fibrosis. Existing treatments, particularly those that treat the primary injury, can allow complete resolution. Although it is likely that newly synthesized collagen may be more susceptible to degradation than old collagen, there is abundant evidence in animal models that even advanced cirrhosis is reversible, and in humans, the data suggest that fibrosis is reversible.
Antifibrotic therapies would target different areas in the fibrogenic cascade, including inhibition of matrix deposition, collagen synthesis, modulation of stellate cell activation, enhancing matrix degradation, or stimulation of stellate cell death or apoptosis. Several drugs with specific ‘antifibrotic activity’ have been studied in human trials but were not proved to be clearly effective.
The ideal antifibrotic agent which is safe, when used over a long time, specific to the liver and nontoxic to hepatocytes, potent, orally bioavailable, and inexpensive is not yet available. Many agents were shown to be effective in vitro and in animal models. Translation of this laboratory success into clinical trials is underway, paving the way for use in human liver disease. Increasingly, multiple-agent strategies that work at different mechanistic levels are likely to be assessed (combination therapy). Evidence of the long-term benefits of the reversal of fibrosis on clinical outcome, such as a reduction in portal hypertension or the rate of development of hepatocellular carcinoma, is needed.Although there are no definite and effective antifibrogenic agents, possible candidates are antioxidants, interferons, flavonoids, renin-angiotensin system inhibitors,endothelin receptor antagonists, and peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists.