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Pirfenidone: a potential therapeutic option in the treatment of liver fibrosis

Chronic liver injury usually leads to a stereotypical response with both wound healing and parenchymal regeneration. Current evidence indicates that liver fibrosis is mediated by myofibroblast-like cells derived predominantly from resident hepatic stellate cells (HSC), although studies have also shown that they may arise from portal myofibroblasts, bone marrow mesenchymal cell progenitors, circulating fibrocytes or by means of epithelial–mesenchimal transition. The HSC are vitamin A-storing cells located in the space of Disse between the sinusoidal endothelium and hepatocytes. After liver injury, HSC are activated, acquire a myofibroblast-like phenotype, proliferate and produce profibrogenic cytokines and enzymes that regulate the catabolism of collagens and other matrix components. Cirrhosis is the most advanced stage of liver fibrosis, but also leads to distortion of the liver parenchyma associated with the formation of septae and nodules, altered blood flow (including intrahepatic portosystemic shunts) and the potential development of liver failure. Once considered irreversible, there are now clinical and laboratory data indicating the potential regression of liver fibrosis and improved outcomes in some clinical situations. The speed of this regression varies and depends on the nature of the matricial components, cellularity, topography and duration of the fibrosis. Unlike the reversibility of the fibrotic component, at least part of which is quite rapidly reversible, the reversibility of structural distortions (particularly, vascular shunts in the portal–central septa and the larger fibrous scars of nodular parenchymal extinction) is so slow that it is unlikely to be completed during a patient’s lifetime. The partial reversal of cirrhosis is associated with the variable resorption of fibrosis and the conversion of the cirrhotic pattern into a hyperregenerative, macronodular, and possibly even incomplete, septal variety. Unfortunately, despite our increasing knowledge of their molecular and cellular aspects, the therapeutic repertoire for the treatment of liver fibrosis and cirrhosis remains limited. The best antifibrotic treatment is elimination of the underlying disease process but, in situations in which this is not possible, specific antifibrotic therapy is desirable. Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone), a small and orally bioavailable molecule, has been proposed as an anti-inflammatory and antifibrotic agent, although its molecular mechanism of action is not clearly understood. In this issue of the Journal, Zhao et al. report that pirfenidone inhibits the liver fibrosis induced by carbon-tetrachloride in BALB ⁄ c mice and by albumin antigen–antibody complex in Wistar rats. It is known that albumin antigen–antibody complex induces inflammation and necrosis in hepatocytes, as well as subsequent HSC activation, mainly through the immune injury–repair mechanism of the host, which has a similar pathway of fibrogenesis to that of human chronic viral hepatitis. Using a human HSC immortalized cell line (LX-2), Zhao et al. have shown that the antifibrotic effect of pirfenidone is mainly through inhibition of HSC activation. Until now, pirfenidone has been evaluated in a small number of patients with fibrosing parenchymal organ diseases. In a pilot clinical trial evaluating the safety and efficacy of pirfenidone, ArmendárizBorunda et al. found a reduction of fibrosis in 30% of 15 patients with established advanced liver disease caused by chronic hepatitis C virus infection by the end of 12 months treatment. However, although promising, these results need to be extended in the context of a double-blind, placebo-controlled clinical trial. One of the major challenges in the field of fibrosis therapy is how to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients. Liver histology is the reference method for staging the hepatic chronic illness and one of the many diagnostic tools used to evaluate and manage patients with liver diseases. However, over recent years, the limited reproducibility of semiquantitative scoring systems interpreting liver biopsy samples, the lack of representativeness of bioptic fragments and the risks associated with sampling have fuelled the proposal of alternative noninvasive biochemical and physical tests. There is no doubt that an understanding of the limitations of each of the elements making up the assessment of fibrosis can help the development of protocols capable of optimizing the information obtained and its reliability. Although Zhao et al. showed that pirfenidone was effective in ameliorating fibrogenesis induced by CCl4 in mice and by albumin complex in rats, their findings remain to be demonstrated in humans using appropriate methodological and technical assessment in clinical trials. It is well recognized that major obstacles to antifibrotic drug development have been the usually slow progression of liver fibrosis in humans (many years to several decades for the developments of cirrhosis, hepatic decompensation or the development of hepatocellular cancer), the complexity of the human system and the lack of sensitive and reliable means to assess fibrosis or fibrogenesis. In addition, the usefulness of in vitro models for drug discovery is limited, because these models do not reflect the complex interactions that govern fibrogenesis or fibrolysis in vivo, such as: (i) contributions of, or interaction with, other cell types; (ii) the many cytokines, growth factors and other mediators that are produced by other cells; (iii) the normal or altered extracellular matrix; and (iv) changes in vascular architecture, oxygen supply and the production of reactive oxygen species. The availability of new methodologies will aid in the clinical development and validation of antifibrotic agents. It is only from this primary point that antifibrotic treatments can be properly evaluated.