There has been a lot of recent interest in the pharma realm regarding nonalcoholic fatty liver disease (NAFLD) and its more advanced stage, nonalcoholic steatohepatitis (NASH). Conservative estimates suggest there are 16.5 million Americans with NASH, which is soon predicted to overtake hepatitis C as the leading cause for liver transplants. NASH is also the cause of an unusually high increase in hepatocellular carcinoma, and with NASH tumors frequently not being found until the late stages, they are often larger and tougher to treat.
NASH has become an area of intense focus at Mount Sinai, in lab and clinic. Dr. Scott Friedman, dean for therapeutic discovery, chief of the Division of Liver Disease, Fishberg Professor of Medicine and a professor of pharmacologic sciences at the Icahn School of Medicine at Mount Sinai, is an internationally recognized key opinion leader in the field of evolving treatments for NASH. He has helped define the biology of fatty liver disease and the associated scarring that can lead to cirrhosis, unearthing novel mechanisms and targets for new therapies. In the lab, he guides preclinical work that is paving the way for several upcoming trials.
Researchers are focused on cost-effective risk stratification strategies, and using all available tools to detect NASH as early as possible. Clinicians rely on FibroScan, a rapid noninvasive tool for assessing NASH risk. With a mobile version of this device, clinicians can travel to clinics throughout the city to detect NASH cases. With a goal of creating an optimal care delivery model, the Mount Sinai Institute of Liver Medicine is participating in a pilot study using FibroScan and associated screening tests in primary care, endocrinology and bariatric care.
DDNews recently spoke to Dr. Friedman in order to elucidate the current work on NAFLD and NASH.
DDNews Magazine: How are nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) generally detected?
Scott Friedman, M.D.: Generally, the diseases are detected incidentally because of elevated liver blood tests (ALT, AST), or because an imaging study of the liver; for example, an ultrasound shows fat. It is important to note that most cases of fatty liver disease are not yet diagnosed, since there are no routine screening recommendations, and we therefore believe there is a huge reservoir of undiagnosed patients in the United States and worldwide.
DDNews: Can you tell us more about FibroScan and how it is used?
Friedman: FibroScan is a bedside device that was originally developed by the French cheese industry to determine the ripeness of the cheese—in essence, it assesses the speed with which a pulse generated by the device travels through the liver, which is created by a handheld probe held alongside the liver. The stiffer the liver, the faster the wave travels. Our clinicians have found it extremely helpful in getting an approximate assessment of whether advanced fibrosis is present. It is worth noting, however, that stiffness doesn’t always result just from fibrosis, and can be elevated due to inflammation.
While FibroScan is a useful bedside test in clinical practice, it is not sufficiently sensitive and specific to be used in determining if drugs in clinical trials are having a beneficial effect. A more sophisticated version of this test, MR elastography, assesses the stiffness over the entire liver and appears to be far more sensitive and specific as a reflection of underlying fibrosis and inflammation.
DDNews: How is NASH associated with diabetes and metabolic syndrome?
Friedman: The driving pathophysiology of NASH is not completely understood, yet most patients [also] have diabetes and metabolic syndrome. We believe that the lipid abnormalities and hyperinsulinemia associated with metabolic syndrome contribute to hepatic fat and inflammation, but the exact mechanism is not fully clarified. Overall, approximately 60 to 70 percent of patients have diabetes. This is a problem not only in the United States, but worldwide. In particular, South Asians have a high propensity to develop diabetes even when not obese, and thus India has a growing prevalence of NASH.
DDNews: What is the most important thing to research and study regarding NAFLD and NASH?
Friedman: There are many areas that demand further study. From a basic perspective, we need to understand better the relative contributions of the different drivers of disease, including insulin resistance, lipotoxicity, altered microbiome, inflammation, cell death and fibrosis. Currently, we do not have a hierarchy of importance of these different abnormalities that are associated with the disease, and it is possible that different patients have different constellations of drivers that create NASH.
From a clinical perspective, we still lack well-validated noninvasive markers that can accurately stage the amount of fibrosis and inflammation. This would be critical information to avoid liver biopsy and to facilitate testing of new drugs and clinical trials. Currently, more advanced clinical trials require liver biopsy, which is invasive and prone to sump sampling variability. We hope that within three to five years, biopsy can be replaced by other minimally invasive methods that can accurately assess the amount of fibrosis and tissue damage.
DDNews: Can you tell us more about the drug trials currently underway at Mount Sinai that are intending to identify a therapeutic target for NASH?
Friedman: I don’t have the complete list in front of me; however, there are literally dozens of new agents being tested in clinical trials, most of which are being done at Mount Sinai as well. They attack a number of different targets of the disease, including fat accumulation in hepatocytes, inflammation and fibrosis. We are rapidly gaining knowledge about the optimal way to design clinical trials, and the optimal patients to choose for such efforts.
DDNews: What is the current status of NASH drug discovery?
Friedman: Please see my Nature Medicine review (Friedman’s paper, “Mechanisms of NAFLD development and therapeutic strategies,” is available at www.nature.com/articles/s41591-018-0104-9). As I noted, there are many targets and new drugs at every stage of development, from animal studies through to Phase 3 trials, that could lead to drug approval. The intense interest by the pharmaceutical and biotech industry reflects both the large market size and unmet need, as well as the prior successes with treatments for hepatitis B and C, which has energized many companies to continue seeking treatments for patients with liver disease of all types.
DDNews: What are the current treatment options for NAFLD and NASH?
Friedman: Because there are no approved pharmacotherapies, the only options are weight loss and exercise. Some evidence supports the use of vitamin E, and some patients are offered this medication or use an over-the-counter preparation. It is unlikely this will sufficiently address the problem, and thus better treatments are needed.
While this all may sound discouraging, it is also important to realize that weight loss, even to a modest extent, can have a significant beneficial effect on NASH severity. Therefore, efforts to achieve modest but durable weight loss remain a mainstay of therapy. In patients who are extremely obese and have other comorbidities, bariatric surgery appears to achieve a benefit in reducing activity and fibrosis; however, liver disease alone is not an appropriate indication for bariatric surgery.
DDNews: What are the genetic and potentially microbiome-related risk factors in NASH progression?
Friedman: This is a critical question, because the disease of NASH—like obesity, which it accompanies—is rising precipitously throughout the world, yet our genetic makeup has not changed for thousands of years. This begs the question, what external factors may have created this new epidemic? It is true that we are less active and many individuals have more high fructose corn syrup in their diet as a sugar substitute. But in addition, there is more widespread use of antibiotics both in the clinical setting as prescription drugs, as well as in the food we eat. Collectively, these evolving changes could have a profound effect on the composition of the gut microbiome.
Indeed, there is strong animal data that suggests that NASH can be transferred to normal, lean mice by microbiome transplantation. The challenge is that we are only now beginning to understand what features of the microbiome confer different risk of diseases, not only in liver but also immune disorders, cancer and infectious diseases, as well as chronic inflammatory states. Ultimately, these early studies of microbiome biology will eventually translate into new diagnostics and therapies that will impact NASH, as well as other diseases.
Genetics are also important, but do not account for most of the risk of the disease and are confounded by the fact that although NASH can run in families, first-degree relatives typically share the same microbiome, so it is difficult to distinguish between effects of genetics compared to a shared microbiome. Still, there are a few genetic variants that have been implicated in elevating the risk of NASH, in particular PNPLA3, which is more prevalent in Latinos descended from Central and South America. We continue to increase our understanding of genetic variants that can confer an increased risk of NASH among those who have other abnormalities, such as altered microbiome or obesity.
DDNews: How variable is NASH progression, depending upon the patient?
Friedman: This represents a major frustration for the field, because the natural history of NASH is not well characterized, and we know that patients can wax and wane in their disease stage and severity. Reasons for this variability are not well understood, and could reflect changes in diet or weight during the course of months to years, but this variability has been a major confounding effect that has made clinical trials difficult. Specifically, many patients on placebo improve, which can confound the interpretation of trial results when compared to a pharmacotherapy.
DDNews: How does NASH cause/contribute to hepatocellular carcinoma (HCC)?
Friedman: All chronic liver diseases are predisposed to hepatocellular carcinoma, especially at later stages. What is particularly worrisome about this cancer in NASH is that a higher fraction of patients present with cancer before they are sclerotic, compared to other diseases. This has important implications for screening guidelines. Because typically HCC is not found upon screening tests in patients with NASH, it tends to present later when the tumors are larger and less amenable to curative therapies.
It is also known that obesity per se confers a high risk of all cancers, which has a number of potential explanations, including increased insulin, insulin growth factor and other systemic abnormalities that are conferred by obesity that may increase cell proliferation, chronic inflammation and risk of cancer. In addition, all fibrotic liver diseases have increased risk of cancer, and the fibrosis itself may be contributing to this risk by altering the health of surrounding cells and predisposing to changes that lead to cancer.
DDNews: Has there been an increase in the incidence of hepatocellular carcinoma since NASH has been on the rise?
Friedman: The rate of rise in HCC among patients with NASH is faster than any other etiology. Still, however, NASH-associated liver cancer represents a minority of the overall number of HCC cases in the United States.
DDNews: Regarding concerns that NASH is poised to overtake hepatitis C as the leading indication for liver transplantation, why do you think this is? How can it be prevented?
Friedman: The rising fraction of patients undergoing liver transplantation for NASH reflects two major trends. First, the tremendous success of antiviral therapies, initially for hepatitis B and now for hepatitis C as well, means that fewer patients with these viral infections will continue to progress because they have been effectively treated. In the case of hepatitis B, current treatments achieve long-term suppression of infection but not cure, whereas the current direct acting antiviral drugs for hepatitis C achieve cure in 95 percent or more of patients. This is a tremendous success story that is leading to steadily dropping numbers of patients who develop advanced liver disease or liver cancer requiring liver transplantation.
At the same time, as noted above, there is a steady increase in both the prevalence of fatty liver disease, as well as the fraction of patients who are progressing to more advanced stages. It is still not uncommon for patients to show up with very advanced fibrosis or cirrhosis, without having realized they had underlying liver disease for many years. In the past, such patients might be called “cryptogenic cirrhosis,” whereas we now realize that a sizable fraction of such unexplained services reflects prior undiagnosed fatty liver disease.
DDNews: Is there anything else you would like to tell us? What do you find most exciting about your recent research?
Friedman: This is an extremely rapidly moving field that has seen early evidence that NASH can be treated, although current response rates are suboptimal. For example, the recent Phase 3 REGENERATE trial by Intercept testing a novel FXR agonist, a obetacholic acid, achieved 23-percent reduction in fibrosis among treated patients, compared to 11 percent in placebo patients. This was highly significant; still, 77 percent of patients failed to achieve a response even in the treated group. This leaves a huge amount of room for improvement.
On the other hand, these data represent the very first time a chronic fibrotic liver disease has been treated without simply curing the underlying condition, as in the case of hepatitis C therapies. It has been very gratifying to be a part of the story from the beginning, because our laboratory tested this drug in animals over 15 years ago, which showed evidence of activity. (Please note that I remain a consultant to Intercept.)
On a personal note, I have been studying the cellular and molecular basis of hepatic fibrosis for over 35 years, and was among the first to characterize the key fibrogenic cell in liver, the hepatic stellate cell. It is enormously gratifying to see the findings we have generated over decades currently translating into new therapeutic targets and drugs. We remain at the forefront of defining mechanisms underlying fatty liver disease and fibrosis, both by performing basic research studies, animal testing of new therapies, and conducting clinical trials with new agents. As a program, our work covers the full gamut of discovery and clinical testing for NASH, as well as other fibrotic liver disorders. It’s a very exciting time, and for sure the best is yet to come.
