Liver Fibrosis: Challenges of the New Era
Article Outline
As hepatologists are well aware, the care of patients with fibrosis is entering a new era. Over the last few decades, the tools available for clinical care, the intellectual framework we use to understand fibrosis, and the list of potential drug targets have changed dramatically. Nonetheless, progress has been frustratingly slow. There are still no effective antifibrotics available and liver transplant remains the only option for many patients. The goal of this commentary is to review recent advances in understanding fibrosis as well as to outline some of the key challenges remaining before effective preventative and therapeutic treatment of patients at risk for end-stage liver disease becomes a reality.
Our perspective on patients with fibrosis and cirrhosis is undoubtedly brighter now than it would have been a generation ago. Better clinical care—including the use of antibiotics, transjugular intrahepatic portosystemic shunting, and β-blockers—and increasingly effective antiviral therapy have resulted in improved outcomes for many patients with chronic liver disease. Advances in liver transplantation have had a similarly dramatic impact on the practice of hepatology.
One of the most exciting and important developments in the field, however, has been the finding that fibrosis can regress. Whereas fibrosis was once viewed as a relentless and progressive process, it is now well established in both animal models and humans that clinically significant histologic improvement can occur even in a cirrhotic liver.1, 2, 3, 4 The mechanism is not fully understood, and therefore it is not known whether significant regression is a realistic goal for patients with end-stage liver disease. Regardless, the stakes for antifibrotic drug development are higher than ever before.
Bench research over the last decade has resulted in several breakthroughs that have dramatically increased our understanding of the mechanisms of fibrosis. In particular, the isolation of hepatic stellate cells, in vitro models of stellate cell myofibroblastic activation, and new insights into the role of the immune system in fibrosis have led to the identification of new therapeutic targets.5 As a result, there are now multiple therapies that have been tested and proven efficacious in animal models.
On the flip side, potential therapies and therapeutic targets identified “at the bench” have not reached the bedside. Although a number of antiviral agents, antidiabetic agents, and renin–angiotensin inhibitors are currently in clinical trials with fibrosis as an end point, there are few novel drugs in the antifibrotic pipeline. Given the regulatory process required for drug approval, it may be years before an antifibrotic is available for routine clinical use.
What are the challenges that must be overcome in the next decade for antifibrotic therapy to become a reality? The need for antifibrotics is great, and the realization that fibrosis can regress suggests that there is a large pool of potential recipients who would derive real benefit from treatment. The number of targets and agents identified through in vitro and animal studies is large, and basic research on fibrosis of the liver as well as of other solid tissues is thriving. In the long term, we should be optimistic about the therapies we will be able to offer our patients in the future. In the short term, several surmountable obstacles stand in the way of bringing antifibrotics to the clinic.
A major challenge in developing new antifibrotics—and to using them in individual patients—is the lack of safe and accurate tests to quantify fibrosis. The many flaws of the gold standard, the liver biopsy, have been extensively discussed in the literature, and it is clear that the biopsy is both too dangerous and too inaccurate to detect the small changes in fibrosis required for clinical trials. Serum tests and noninvasive imaging modalities (including transient elastography and magnetic resonance elastography)6, 7, 8 are safe and may be useful adjunct diagnostic tools in individual patients, but at this time lack the required accuracy for trials and are not widely available. New methods, including blood tests that measure fibrogenesis and fibrolysis, and better radiologic tests (eg, sophisticated new applications of magnetic resonance imaging) could have a dramatic impact on the ease of bringing drugs to market.
A second major challenge to developing antifibrotics is the need to identify patients who are most likely to respond to a particular drug. Although fibrosis was once believed to progress via a single common pathway, etiologic differences in the mechanism of fibrosis are increasingly appreciated, and it may be that there is no single antifibrotic appropriate for all patients. Similarly, genetic differences among patients may be important determinants of the progression of fibrosis and the response to a specific drug. Although the individualized medicine promised by the genomics revolution is not yet a reality, there are now several genetic markers that have been identified and that predict increased susceptibility to fibrosis.9 The identification and careful validation of additional markers will be critical to antifibrotic development.
Finally, identifying antifibrotics and bringing them to clinical practice will require continued creativity and cooperation among clinicians, academic researchers, and pharmaceutical companies. Preliminary findings suggest that this has already begun to happen. As it continues, we can be confident that antifibrotic therapy will soon be a reality for our patients.
References
- . Reversal of fibrosis: no longer a pipe dream?. Clin Liver Dis. 2006;10:481–497
- . Reversal of hepatic fibrosis—fact or fantasy?. Hepatology. 2006;43:S82–S88
- Mechanisms of spontaneous resolution of rat liver fibrosis (Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors). J Clin Invest. 1998;102:538–549
- . Regression of human cirrhosis (Morphologic features and the genesis of incomplete septal cirrhosis). Arch Pathol Lab Med. 2000;124:1599–1607
- . Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655–1669
- . Noninvasive assessment of liver fibrosis and portal hypertension with transient elastography. Gastroenterology. 2008;134:8–14
- . Elastography for detecting hepatic fibrosis: options and considerations. Gastroenterology. 2008;135:299–302
- Magnetic resonance elastography for the noninvasive staging of liver fibrosis. Gastroenterology. 2008;135:32–40
- Recognition of genetic factors influencing the progression of hepatitis C: potential for personalized therapy. Mol Diagn Ther. 2008;12:209–218
The author discloses no conflicts.
PII: S0016-5085(08)02207-5
doi:10.1053/j.gastro.2008.12.028
© 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
