Liver fibrosis is a repair response to chronic liver injury caused by various causes, which can lead to massive deposition of collagen and other extracellular matrix. Various cells and cells, cells and matrix, matrix and transmitters in the liver constitute a complex network system, which jointly participate in the occurrence and development of liver fibrosis. During the annual meeting of the Asia-Pacific Association for Liver Disease Research (APASL), Professor Scott Friedman, Icahn School of Medicine, Mount Sinai, USA, gave a keynote report "Mechanisms of Fibrosis Progression and Targets of Therapy". In this issue of Hepatology Digest, we are honored to invite Professor Scott Friedman to share further on this topic.
IH: As we all know, you are the founder of the international research on liver fibrosis. Please introduce the research progress of the pathogenesis of liver fibrosis in recent years?
Prof. Friedman: Very hard to summarize in a short amount of time, but we now have very deep understanding of the cell types that make fibrosis in liver. Primarily, it is the hepatic stellate cell which becomes activated and turns into an activated myofibroblast. In chronic liver disease, myofibroblasts are the major target of antifibrotic therapies—and that's a major advance. We also know the source of the myofibroblast in other forms of liver disease, such as biliary fibrosis. We know the mediators that drive activation of myofibroblasts. And most recently, we've learned a lot of information about the heterogeneity of activated myofibroblasts based on very elegant studies using single cell RNA sequencing.
So, we're really going to have a very deep and comprehensive understanding of stellate cell biology and that really forms the basis of clarifying the role of fibrosis. At the same time, we are also learning more about the signals that drive fibrosis that emanate from hepatocytes, inflammatory cells, and other resident liver cells including, sinusoidal endothelial cells. So we're continuing to gather a very comprehensive picture of both the signals and the cell types that drive hepatic fibrosis.
IH: What important role does hepatic stellate cell (HSC) play in the whole dynamic process of liver fibrosis?
Prof. Friedman: The hepatic stellate cells certainly is in the center of pathogenesis of fibrosis. Not so much when it is quiescent, but when it becomes activated it becomes a source of extracellular matrix proteins, as well as inflammatory and fibrogenic mediators that influence other stellate cells and also talk to surrounding cells—in particular sinusoidal endothelium. So, stellate cells are absolutely at the center of the dynamic of liver fibrosis.
IH: Besides the gold standard liver biopsy and some imaging methods such as transient elastography, are there any promising molecular markers for diagnosis and monitoring?
Prof. Friedman: In terms of molecular markers, there's a lot of activity and a lot of progress. So far, we do not yet have a marker that can replace biopsy for clinical trials, but we're getting closer. Starting with blood tests, we have some well-known blood tests, such as the FIB-4, the ELF marker, PRO-C3. But, in addition now, there are at least 2 different platforms for measuring aggregate serum proteins called proteomics. So there are now proteomic studies in blood.
The other group of diagnostic modality—so it's coming quickly and improving—are imaging tests, particularly MR elastography and MR fat fraction, as well as corrected T1 weighted imaging. All of these imaging tests are becoming much more useful in assessing the severity of liver disease and the amount of fat. There are diagnostic tests now that can measure liver function. One is called HepQuant, which measures the metabolic reserve of the liver. And there are now tests to measure serum proteolytic activity from a company known as Glympse Bio.
And finally, when biopsies are performed, there are now a number of artificial intelligence-based methods that can, in much more detail, measure different components of the biopsy using different techniques that give a much more comprehensive and quantitative picture of both the cells and the structures within the liver biopsy. So, a lot of progress. The hope is that we will be able to avoid doing biopsy altogether to stage disease, and this will be very helpful in accelerating the development of clinical trials.
IH: What are the potential drugs of reversing liver fibrosis? How long is the way to clinical application for them?
Prof. Friedman:In terms of potential drugs to reverse liver fibrosis, there are probably about 12 drugs that are in phase III trials now, another 50-60 drugs in phase II. So, a lot of exciting new drugs. None of them have been approved yet. In phase III, we have FXR agonists, thyroid hormone beta agonists, FGF21, FGF19, in addition to a growing list of PPAR agonists—particularly, pan-PPAR agonists, PPAR -alpha -delta -gamma agonists. I already mentioned FXR agonists. And then, also, in phase III now is a drug called Aramchol that blocks stearoyl-CoA desaturase-1 and reduces liver fat. In phase II, there are other drugs to reduce liver fat, such as an ACC inhibitor, a fatty synthase inhibitor, and, most recently, a drug that is going into phase II being called Icosabutate that has an exciting ability to improve liver tests and may help in resolving NASH.
Beyond that, there are too many drugs for me to actually list altogether. But a lot of excitement, a lot of drugs. We are very, very close. I think within 2-3 years, we may see a drug approved for NASH. Certainly, a better cholic acid looks promising. And now, the FDA is reviewing the possibility of approving a better cholic acid, which is an FXR agonist. So, you know, that's a short version of what is now a very comprehensive list of potential drugs.
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