Editor's note: Liver fibrosis is an abnormal hyperplasia of connective tissue in the liver caused by a variety of complex factors (inflammatory stimulation, viral infection, autoimmune injury, etc.), which can further develop into cirrhosis or even liver cancer under chronic and repeated pathological stimulation. At the same time, liver fibrosis is a dynamic process of liver scar repair, characterized by the net accumulation of extracellular matrix, which is the common outcome of the progress of various chronic liver diseases. So far, there is no effective drug for anti-fibrosis treatment. At the 32nd annual meeting of the Asia-Pacific Association for Liver Research (APASL), this journal had the honor to interview Professor Scott L. Friedman, an important founder of the field of liver fibrosis and professor of Icahn Medical College in Mount Sinai, USA, to share the important research progress, clinical transformation and application and challenges in the field of liver fibrosis.
IH: As we all know, liver fibrosis is the key link in the development of various chronic liver diseases to cirrhosis. What is the current status of screening, diagnosis and treatment of liver fibrosis?
Dr Friedman: This is a very exciting time with a lot of progress in both understanding the basis of fibrosis, and translating those insights into novel diagnostics and treatment. Most of the attention around hepatic fibrosis is focused currently on non-alcoholic steatohepatitis and alcohol-associated liver disease, since these illnesses have a rising prevalence throughout the world. Therefore, efforts to enhance screening and diagnosis are primarily focused on this disease - fatty liver disease, from either obesity or alcohol. A number of both serum markers and imaging technologies are developing rapidly to non-invasively screen and stage fibrosis. For example, blood testing, including ELF, FIB-4, PRO-C3 and NAFLD fibrosis score, can be used in combination with other imaging tests to diagnose fibrosis. Those imaging tests can include MR elastography, corrected T1-weighted imaging or bedside transient elastography. Collectively, these findings with non-invasive techniques will eventually replace liver biopsy to score fibrosis. However, current approaches for clinical trials of new drugs generally require liver biopsy to assess whether a drug is improving fibrosis. Speaking of treatment, there are new drugs that are likely to be approved for NASH in the next 6-12 months. In particular, thyroid hormone beta agonists and FXR agonists look promising based on data from phase III trials. This, however, is only the beginning. There will be many new advances in screening, diagnosis and particularly in the treatment of liver fibrosis associated with fatty liver diseases, but also with viral hepatitis from hepatitis B, C and delta (D).
IH: For a long time, we still lack effective treatment drugs for liver fibrosis. What do you think are the challenges we face?
Dr Friedman: There are many challenges to approval of effective anti-fibrotic drugs. First is to completely understand the pathogenesis of fibrosis, which we now think is attributable to activation of stellate cells into myofibroblasts. Next, we need to identify the appropriate therapeutic targets and test them in animal models before trying them in human clinical trials. There are challenges because animal models tend to be more optimistic in predicting response to therapies than human trials demonstrate. So we need to better translate efficacy in animal models to whether they are effective in human fibrosis. Another challenge is that fibrosis generally progresses slowly in man, so clinical trials seeking to show a benefit on fibrosis need to be at least one year or longer, and generally require a biopsy to establish improvement in response to those therapies. We need to shorten the trial length by using non-invasive markers in addition to, or instead of, liver biopsy. Finally, treatment of fibrosis in fatty liver disease and NASH is also challenging, because patients have multiple other illnesses, including diabetes, hypertension and coronary artery disease, and so there are competing comorbidities, and patients are typically on many drugs at the same time, which is challenging for compliance, and also to minimize the risk of drug-drug interactions.
IH: In recent years, with the gradual deepening of research, the formation mechanism of liver fibrosis has gradually become clear. Please introduce your latest understanding of the formation mechanism of liver fibrosis?
Dr Friedman: In answering this question, I want to focus primarily on recent data from my laboratory performed largely by Dr Shuang Wang, a faulty scientist in my division. We showed that as fibrosis progresses, the behavior of hepatic stellate cells changes progressively to develop long foot processes and physical interactions that lead to increased autocrine signaling between stellate cells, rather than between stellate cells and macrophages. This transition from a macrophage-rich to a macrophage-depleted microenvironment means that the therapies for fibrosis may differ depending on how advanced the disease is. Earlier stages of fibrosis may include targets against inflammation, whereas later stage fibrosis may require targeting of molecules that drive autocrine signaling of stellate cell activation. This may explain why anti-fibrotic therapy is more difficult in cirrhotic patients. Also in cirrhosis, patients have extensive cross-linking of their scar, which makes the collagen relatively insoluble. Physical changes in the architecture of the liver make delivery of effective drugs more challenging due to altered microcirculation. Despite these challenges, I am confident that we will continue to make progress in identifying the most potent therapeutic targets, and improve the outcome for patients with advanced liver fibrosis.
IH: Finally, please introduce your understanding of the formation mechanism of liver fibrosis. What important molecular biological processes can be used as potential strategies for the treatment of liver fibrosis?
Dr Friedman: Currently, most promising therapies for fibrosis are actually changing the level of inflammation and hepatocellular injury, and are not directly anti-fibrotic, but rather indirectly, through the attenuation of cell death, injury and inflammation. Increasingly, we are gaining a better understanding of the biology of fibrosis directly - the cell surface receptors and the circulating cytokines that drive fibrogenesis. As we identify new cell surface molecules and regulatory events in stellate cells, as well as the secreted molecules that drive fibrosis, we can anticipate more therapeutic targets that directly attack the basis for fibrogenesis and can regress scar, even in advanced liver disease. I am very optimistic that just as we have seen tremendous progress in the last 25 years, we will enjoy even greater insights and progress that will lead to effective anti-fibrotic therapies in the coming years. This will greatly improve the outlook for patients with liver disease throughout the world, which includes millions of patients, both in the West as well as Asia, and China in particular.
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