Reversibility of hepatic fibrosis and cirrhosis—is it all hype?(u may find useful)

[devildoc]

The idea that hepatic fibrosis is reversible is taking root, many clinicians are beginning to ask why, if fibrosis is reversible, is there so little progress in the clinical setting, and will patients ever really benefit from antifibrotic therapies? Underlying such questions is a subtle cynicism that the reversibility of fibrosis and cirrhosis has been overhyped—yet another example of the medical media 'spin machine' giving false hope to desperate patients. The situation has been fueled by the actions of ambitious institutional press relations officers. One such example is the worldwide media focus on the use of sulfasalazine to treat hepatic fibrosis, with claims that half of all liver deaths could be avoided even though the drug's reported efficacy was based on a single study in rodents.
So what is the truth, and how do we maintain perspective? First of all, progress has been tremendous. The mere idea that fibrosis can regress when the initial disease is controlled or cured is exciting, given the decades of dogma that suggested scar formation was a unidirectional pathway. Ample evidence that fibrosis regresses with control of hepatitis B, hepatitis C, or other chronic liver diseases attests to the tremendous regenerative power of the liver, and the rapid progress made in the development of targeted antiviral and disease-specific treatments. Without such advances a discussion of reversibility would have been moot, but this discussion has raised some semantic issues that sow controversy and obscure continued progress. Specifically, use of the term 'reversal' implies a complete return to normal histology, whereas a better term would be 'regression'—a more accurate and relevant term that indicates improvement in fibrosis without necessarily a return to normal histology. Of equal importance, stasis of disease or delayed progression are clinically meaningful, as they might prevent the development of cirrhosis, which is the only stage of chronic liver disease associated with significant and predictable complications. A related issue is the failure of some clinical studies to distinguish between cirrhosis, which connotes distinct architectural and structural changes (including nodules of fibrosis that encapsulate hepatocytes), and advanced fibrosis, which lacks these features.
We are approaching a situation with hepatic fibrosis somewhat like that observed for cancer, where progress in curing disease in rodent models has been far more rapid than in humans. What is so different about hepatic fibrosis in rodents? The answer could lie primarily in the speed of disease progression, which in rodents occurs in weeks after toxin administration (e.g. carbon tetrachloride, thioacetamide, dimethylnitrosamine) or bile-duct occlusion, whereas in humans it typically requires decades. During that protracted interval in humans, there is ample time for collagen crosslinking by tissue transglutaminase, septal thickening, and progressive acellularity, features associated with less-reversible disease in animal studies.Fibrosis resolution in rodent models occurs through conversion of micronodular to macronodular cirrhosis and thinning of septae.Micronodularity and thickened septae in humans might, therefore, reflect advanced, less-reversible disease, a conclusion underscored by the finding that these features correlate with increased severity of portal hypertension in patients with cirrhosis.
This observation raises another challenging paradigm shift brought about by the growing evidence of fibrosis regression, namely that not all cirrhosis is the same; in fact, patients with cirrhosis can experience a widely variable clinical course. Our current staging methods do not, however, discriminate sufficiently between different degrees of cirrhosis. This oversight is understandable because until the past decade it hardly mattered whether a patient had 'early' or 'late' cirrhosis—their only viable option would be liver transplantation, indicated solely when hepatic decompensation occurred. Moreover, of the several histologic scoring methods, only the Ishak staging system has two cirrhosis stages rather than one, and it has been unclear whether these two stages correlate with different clinical outcomes or risk of deterioration. Indeed, given the significant sampling variability of liver biopsies, standard fibrosis scoring systems might never be adequate to predict clinical outcomes. Other approaches to stage the extent of liver injury and fibrosis are, therefore, being developed, such as assessment of the number of activated stellate cells by smooth-muscle actin staining,determination of tissue elasticity using a noninvasive probe, quantifying metabolic activity by a breath test or multiplex serum marker panels. Alone or in combination, these tests will substantially improve our ability to predict prognosis, enabling us to select patients for optimum antifibrotic or disease-specific treatments, or liver transplantation. In fact, assessing fibrosis histologically could become obsolete unless we develop methods that can be used to quantify the chemical or structural reversibility of the hepatic scar that correlates with response to therapy and reversibility, for example by assessing the extent of collagen crosslinking.
Another parallel between advances in fibrosis research and in cancer research lies in their incremental nature, such that progress can best be appreciated in hindsight. One need only look to the examples of breast, prostate and hematological malignancies to appreciate how significantly their outcomes have improved through sensitive detection and improved therapies based on a clear understanding of their pathogenesis. Similarly, without effective antiviral drugs for hepatitis B and hepatitis C, liver fibrosis reversibility would never have been imagined. Now, however, the challenge is to prove that fibrosis can be reversed by a direct attack on the pathways of fibrogenesis and matrix degradation, instead of therapy directed only to the primary cause of liver disease. Ample therapeutic targets have been identified and there are many drugs in development that could establish a 'proof of concept' provided that clinical trials are thoughtfully designed and of sufficient duration, end points of efficacy are sensitive and robust, and cohorts are appropriately stratified based on disease risk. To accomplish appropriate stratification, genetic risk markers are being uncovered that should enable clinical trials to distribute patients of comparable fibrosis progression risk equally into both treatment and control groups. In addition to genetic markers of disease progression, improved antiviral therapies could allow us to define genetic rather than histological markers of disease regression, because an increasing fraction of patients will be able to clear or suppress their chronic HCV or HBV infections, thereby enabling fibrosis to regress.
So, hindsight indeed provides ample evidence of gratifying progress in hepatic fibrosis. Continued evolutionary development that changes our thinking about fibrotic liver disease and its prognosis is likely in the future. Revolutionary advances would certainly be welcome, but slow and steady gains should still justify hope without provoking hype.