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NASH

Unravelling the complexity of liver disease with genomics.

We talk to Dr. Scott Friedman, internationally renowned physician and scientist, who explains why Non-alcoholic steatohepatitis or NASH is a liver disease that is becoming a growing health concern world-wide. Dr. Friedman describes the extraordinary capacity for the liver to regenerate, his ground-breaking research into the cause of inflammation and resulting scarring or fibrosis of the liver, and how Whole Genome Sequencing is being used to improve our understanding of why some people have a higher risk of developing the condition than others. Finally, he talks about how drug companies are leveraging all of this growing information in order to develop better diagnostics and new effective treatments for NASH and other forms of chronic liver disease.

Podcast Episode Transcript

April 2021

An interview with Dr Scott Friedman, Dean for Therapeutic Discovery, and Chief of the Division of Liver Diseases, at the Icahn School of Medicine at Mount Sinai, New York City.

Elaine Quinn

Non-alcoholic fatty liver disease or NAFLD is an umbrella term used for a number of conditions of the liver that are not caused by alcohol.  Non-alcoholic Steatohepatitis or NASH is the more severe form of NAFLD and is a growing health concern world-wide. Today we have a very special guest who will shed some light on this potentially life-threatening disease. Dr Scott Friedman is Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases, at the Icahn School of Medicine in Mount Sinai in New York City.  An internationally renowned physician and scientist, Dr Friedman has received multiple awards for his pioneering research into the underlying causes of scarring, or fibrosis associated with chronic liver disease, affecting millions worldwide.

Dr Friedman, it’s a pleasure to welcome you to this episode of In Sequence.

Dr Scott Friedman

Delighted to be here, Elaine.

Elaine Quinn

So, why medicine and why liver disease? Can you give us a little bit of background on how you’ve arrived at where you are today?

Dr Scott Friedman

I’ve been a liver specialist since 1985 when I completed my fellowship at University of California, San Francisco. But my passion for liver disease actually dates earlier to my second year of Medical School when a couple of renowned faculty here at Mount Sinai where I was a medical student gave lectures on the liver that absolutely captured my imagination. I found it fascinating, and it was clear there was a lot to learn. And so, from that point onward I’ve been fascinated by the liver. I remain completely transfixed by its complexity and the majestry of what it does, and it’s been a wonderful career track.

Elaine Quinn

Great and it really is such a complex and an incredible organ, isn’t it, and impacts the body in so many ways, because of the number of functions it’s responsible for. And so, to maybe help us better understand what NASH is in the context of the spectrum of conditions that fall under Non-alcoholic fatty liver disease or NAFLD – can you maybe break it down for us and tell us why it is such a growing concern for public health worldwide?

Dr Scott Friedman

Of course. NASH refers to non-alcoholic steatohepatitis and, as you implied in your opening comments that’s part of a larger umbrella category, known as non-alcoholic fatty liver disease. It’s astounding now there are more patients who are obese in the world than are undernourished and with that obesity comes a rising risk of complications, including type 2 diabetes, hyperlipidaemia, and non-alcoholic fatty liver disease (NAFLD). In fact, the worldwide prevalence of NAFLD is around 25%. That’s an astounding number. Now, not every patient with NAFLD has the more inflammatory form of the disease known as NASH or non-alcoholic steatohepatitis. Probably somewhere around 20-25% of those with NAFLD have this more aggressive inflammatory form of the illness. And that’s the population we’re very concerned about because first of all, the numbers are growing. Secondly, we’re early in the epidemic, so to speak, so most patients who are developing NASH now are still years away from getting worse, but the disease in many patients does progress. It is associated with progressive inflammation and scarring. That scarring can lead to an end stage liver disease state, known as cirrhosis. And both with advanced scarring or fibrosis and with cirrhosis comes an accruing risk of hepatocellular carcinoma or primary liver cancer. And one of the challenges beyond managing NASH and its complications is that patients with NASH have a higher risk of developing cancer before they are at their very late stages than other etiologies of liver disease like hepatitis B and C. And so, we need to be thinking about the risk of cancer in NASH patients, even before they’re diagnosed as being cirrhotic, otherwise they show up too late and the cancers are not curable.

Elaine Quinn

Okay, and so a lot of this really is considering the high-risk factors that you mentioned there. So, we know that modern lifestyles are a major contributing factor to the rise in the numbers of people developing NASH because of problems like obesity or diabetes. And so, these are all the high-risk factors for this condition, but then some people can develop NASH even if they don’t have any of these more common or known risk factors, what can you tell us about that?

Dr Scott Friedman

What you are referring to as a subgroup – a minority, but an important one, of patients who have so called ‘lean NASH’, meaning there are fewer of the conventional risk factors, and yet they have features and liver of NASH. Those patients are as at equal risk of those who are obese with NASH and progressive liver disease, so this condition needs to be taken seriously. And of course, whereas in patients with NASH who are obese, weight loss becomes a very important component of therapy, that isn’t an option of course for patients who are lean. Now it’s worth emphasizing that while obesity is clearly a major risk factor both for diabetes and hyperlipidaemia as well as NASH. There are other potential changes in our world that have contributed to the rising prevalence of NAFLD.  In particular, there’s some very compelling work that suggests that the nature of our gut bacteria or our microbiome may be evolving as a population over time and evolving towards one that is more likely to foster the accumulation of fat and the complications of fatty liver and diabetes. Why the microbiome has been evolving is not entirely clear, but some have speculated reasonably that the widespread availability of antibiotics, not just in clinical use for human diseases, but also in the food that we eat through animal feed and plant-based fertilizers, the growing prevalence of antibiotics has slowly but surely changed our microbiota and that has led to one that seems to favour the accumulation of fat.

There are also important components of our genetics that we don’t entirely understand. There are some you know solid; I would say early work identifying some genetic risk factors. And whether those genetic risk factors also are important in the genesis of lean NASH remains to be established, but one has to assume that there are genetic drivers in all patients with NASH that contribute to the overall state of disease. And one other important component is – to return to the microbiome story, the risk of NASH among first degree relatives, is quite high for patients. If patients have advanced fibrosis there’s a 70% chance that their first-degree relatives will also have some element of liver disease. Now the easy conclusion is to say, well, they have the same genetics and that’s certainly going to be contributing but let’s remember that first degree relatives often live under one roof. And therefore, they’re likely to share the same microbiome. So, there’s a lot of mysteries about the rising prevalence of the disease. I’ve tried to highlight a few of them, but we have a lot to learn about this illness.

Elaine Quinn

That’s really interesting. And with so much to learn about this condition, diagnosis must be quite a challenge. So, what kinds of signs and symptoms are people with suspected NASH presenting with?

Dr Scott Friedman

Well, in terms of the presentation, or the signs and symptoms, in fact most patients with NASH or NAFLD don’t have any symptoms that they can directly attribute to the liver. At most, they may feel tired; they may have a fullness or discomfort in under the rib cage or on the right-hand side where the liver sits. But certainly nothing that jumps out and says, you know there’s a liver problem here. And so, it’s often undiagnosed and it’s very hard to link those symptoms, specifically to the liver. In general, and in NASH in particular, symptoms are not terribly specific and not terribly helpful, which is why most of the cases end up being picked up when the primary doctor does routine liver tests or in the patient with diabetes. So, for example as associated with the obesity epidemic is an epidemic in type 2 diabetes, which is associated with obesity. And we’ve actually, along with many other centres, have begun to screen our diabetics to see if they have liver disease because we know that the prevalence of underlying liver disease in type 2 diabetes is well over 50%, probably close to 70%. And so, one other way to suspect underlying NASH, is if you have a patient with type 2 diabetes, we believe that all those patients should be screened, at least with an ultrasound and liver tests. And we also do another bedside test that’s widely accepted both here and in Europe, known as the fibroscan. That’s a commercial name. The technology, more broadly, is ‘transient elastography’ and what these techniques do is they literally measure the stiffness of the liver. It’s a bedside or you know bench side test that’s done in the outpatient setting. And in patients in whom we suspect they might have liver disease, in addition to ultrasound and liver routine liver chemistries, we’ll usually get a fibroscan as well just to get us a sense of whether they might have underlying scarring and inflammation. There are also blood tests that can be used as screening modalities, the ELF test the FIB-4 test. There is a company known as Nordic Biosciences they have what’s called the PRO-C3. So, there are a number of fairly conventional blood tests that can also be used to heighten the specificity of diagnosing NASH. Ultimately in patients who you strongly suspect have NASH, particularly if you’re contemplating enrolling them in a clinical trial, we recommend liver biopsy, but we certainly don’t jump to do liver biopsy in a patient who we think has NASH, unless it’s going to yield actionable information, either in terms of ruling out another disease or in terms of qualifying the patient for a clinical trial.

Elaine Quinn

And so, you mentioned the genetics or genetic predisposition potentially for developing NASH. So, is genomic research then helping us to understand a little bit more about how much that might be contributing to it?

Dr Scott Friedman

Certainly – genomic research is critical, both to identify and stratify risk, but also to give us unexpected insights into the pathogenesis of the disease. There are a growing list of genetic variants that are associated with risk or prevalence of NAFLD and NASH. And each one tells us something we didn’t know previously about how the body responds to NASH; how the liver metabolizes fat; how it responds to the many drivers that may be predisposing to NASH. And a lot of the genetics is reflected in different risk across different ethnicities. So, for example in North America individuals of Hispanic descent have a higher prevalence of a variant of a gene known as PNPLA3. And seminal work by Dr Helen Hobbs and her colleagues at UT Southwestern first described the risk factor of the PNPLA3 gene variant and then went on to help us understand why that variant predisposed to higher risk of NAFLD. And so, the PNPLA3 variant is thought to be one of the reasons why Hispanic Americans are at higher risk for NASH, and on the other end of the spectrum, African Americans seem to be at a lower risk of NASH even if they harboured some of the known risk factors, including obesity, hypertension, and hyperlipidaemia. Genetic research is absolutely vital to helping us both identify patients who might be at risk because of the variants that they carry in their genome, but also to uncover new pathogenic pathways that could unearth new therapeutic targets.

Elaine Quinn

And that was my next question then. Obviously, a huge amount of the management of this condition would be around prevention and looking to see how we can improve people’s lifestyles and that leads into the kind of treatments that are available in addition to those kinds of preventative measures and how Whole Genome Sequencing might be helping to inform drug development.

Dr Scott Friedman

Certainly, in the case of the variants that have been discovered so far PNPLA3 is one. Another more recent variant that’s extremely interesting is in a gene known as HSD17B13. And the variant that protects patients from NASH seems to encode for an inactive form of the gene product which suggests that when the gene and its protein product are active it is generating more NASH. The obvious implication therapeutically is maybe we can artificially lower the expression of that gene or the protein product, thereby mimicking the genetic protection that’s conferred by the protective variant. That’s just one of many examples where sequencing can make a difference. Now admittedly, the vast majority of sequencing that’s been done in this disease has been Whole Exome Sequencing. As you and maybe your listeners know, exomes are the protein encoding region of the genome. It’s a small fraction mathematically or numerically, but it does carry a lot of the variants because that immediately literally translates into a different protein when there’s a different gene variant in the exome. But it’s clear that there is a lot of additional embedded information when we go to the extent of Whole Genome Sequencing because now, we’re capturing sequence variants that may be in regulatory regions that change the expression of a gene and could be actionable in terms of new therapeutic targets.

Elaine Quinn

Then just to maybe talk a little bit about your own research which has been widely acknowledged and recognized, particularly your work around the processes involved in scarring and fibrosis of the liver tissue. Can you talk a little bit about what your own research has uncovered and what you’ve been working on?

Dr Scott Friedman

Sure, scientists always love to talk about their own work so that’s not a hard one. But it does start back in the early days that I referred to. I’ll take a little stroll down memory lane. When I was a liver fellow in San Francisco at UCSF in the early 80s, we certainly knew about cirrhosis and the dogma was that once a patient develops advanced scarring or even cirrhosis that it’s irreversible and that you have static scar that continues to accumulate. And there was very little appetite for trying to understand the basis for that scarring. It was just sort of accepted as a fact of life when there’s inflamed tissue. But I set about under the guidance of a wonderful mentor Dr Monty Bissell to reassess the whole situation and start with the simple question of where does the scar come from in these liver diseases? Conventional wisdom was that it came from the hepatocytes which are the major epithelial workhorse cell of the liver. And in fact, I started my project under the notion that in fact we would find out how hepatocytes made collagen. And yet I spent six months trying to flog hepatocytes in culture dishes into making collagen and the amount they made was so small that I felt I was barking up the wrong tree.

And so, we took a look at the literature and there was a lot of circumstantial evidence that there was another cell type that was also a resident cell in the liver that normally stored vitamin A droplets as lipids. And that went by various names, but we now call it the hepatic stellate cell. And we developed a method to exploit the buoyancy of these cells because they contained lipid to generate or develop a gradient method to isolate the cells. And once we could isolate these cells, we could then establish that they made fibrosis or scar. And I’m proud to say that really was a critical entry point for the field in being able to reassess how scar is made, how it’s regulated. And over the course of the last 30/35 years both my work and the work in the field has begun to dissect out the pathways that drive scar formation in this the cell type – what turns a cell on; what turns a cell off; how do we get rid of the activated cells; how do the cells when they’re activated in injury make more inflammation and amplify the damage? And all of those questions are now being tackled by hundreds of labs around the world, using very sophisticated technologies, including single cell and single nuclear RNA sequencing.

And most importantly, all of that has translated into an extremely fertile area for drug development. Because many studies in NASH have now shown conclusively that of all the different features in the liver under the microscope for liver pathology of NASH, the one feature that correlates with risk of outcomes or deterioration is the amount of scar. And so, all therapy directly or indirectly has to ultimately culminate in a reduction or regression of scar in the liver. Either by directly attacking the scar-forming cells, those activated stellate cells or by turning off the upstream drivers; the signals, the inflammation, the injury signals that derive from inflammation that ultimately turn on the stellate cell. And so, for me personally it’s been an extraordinary and very gratifying journey, where we started with a concept that was a little radical at the time and over the course of decades has become not only mainstream but has become a fertile source for new drug targets. And so my career has evolved to keep pace with those changes that started with basic work, and then went into more understanding about signalling and how the stellate cell responds, then developing animal models to mimic NASH and, most recently I spend a lot of time talking to different companies about developing new diagnostic tests for NASH and, more importantly, new therapies that really leverage the growing information that we’ve gleaned about inflammation and fibrosis in the liver, in particular, in NASH, but also relevant to other forms of chronic liver disease.

Elaine Quinn

That’s incredible and wonderful to hear how your work is having an impact on so many. And it also surely would have informed as well, the amazing thing about the liver and how it regenerates itself, as you mentioned. So, I guess that’s the silver lining in all of this then, is that in developing new drugs, that it is possible to undo the damage that’s been caused.

Dr Scott Friedman

Yes Elaine, that’s a really great point and it really highlights one of those early clues that made me so fascinated about the liver, is this unique, and still not well understood capacity of the liver, much more than any other organ, to regenerate.  Simply put you can literally resect two thirds of a healthy liver in humans or in mammals and the liver will grow back. And we use that therapeutically to help in liver transplantation.  There’s a procedure surgeons can perform called the living donor transplantation, where a healthy individual voluntarily donates a portion of their liver, to help replace an injured liver often in a family member or a loved one, but not necessarily. And we couldn’t do that if not for the liver’s capacity to regenerate. Now what happens over time is as the scar and the inflammation continue to accumulate, the more fibrosis, the less capacity for regeneration. And yet, because the liver has this unique capacity to regenerate, the natural history of most of these chronic inflammatory diseases is decades not years. And that’s in sharp contrast to other scarring conditions in other organs. So, for example, at the other end of the spectrum is idiopathic pulmonary fibrosis or lung fibrosis.  Patients with lung fibrosis have a tremendously grim prognosis in many cases, where the mortality can be upwards of 50% in four to five years. And while we don’t know why it’s such a more catastrophic and shortened disease in lung compared to liver, I would reasonably speculate that the lung doesn’t have anywhere near the regenerative capacity of the liver. So, once an injury takes root and scarring becomes prominent within the tissue, there’s no capacity to undo that. If you contrast that to liver, not only does the unique regenerative capacity of the liver play out in terms of a longer duration of disease before finally the liver fails, but it also means that if we find effective treatments that really turn off the spigot of inflammation and injury, the liver naturally will start to resume or restore its normal structure and function. And the clearest examples now are in the setting of chronic viral hepatitis either hepatitis B, where we have highly effective suppressive antiviral therapies or hepatitis C, where we have even better, we have curative antiviral therapies. What’s become very clear in using these drugs effectively over the last 10 years is that if you completely suppress hepatitis B or cure hepatitis C, very advanced scar begins to regress entirely on its own. And that obviously translates into a normal, in many cases, a normal life expectancy and attenuated or completely eliminated risk of liver cancer and a completely transformative outlook. It’s certainly been in my career, the most stunning advance in clinical hepatology the ability to cure hepatitis C, which affects 4 to 5 million Americans and many more worldwide. Of course, that shines a light on the challenges of NAFLD because if we looked at the numbers in the States, as I said, the American prevalence of hepatitis C was somewhere in the 4 to 5 million at most. The prevalence of NASH, not just the NAFLD umbrella but NASH, the more serious stage, is 5 to 6 times that.  That means somewhere in upwards of 25 to 35 million Americans are at significant risk of injury, inflammation, fibrosis, and the complications that I’ve been talking about. And so, the scale of the challenge and the unmet need in NAFLD, and particularly in NASH, is far greater than what we have experienced for hepatitis C.

Elaine Quinn

Yeah, those numbers are pretty staggering really, and it presents a huge challenge then for physicians like yourself.  And how are these advances in research; the use of a Whole Genome Sequencing or these recent discoveries – how is it being translated then into the clinical setting?

Dr Scott Friedman

Let me start from the beginning, there are no approved therapies for NASH, and our problem right now is to educate our providers to even consider the disease and to take it seriously when they suspect it in a patient. So, while I’ll get to your treatment question in a minute, let’s focus on the most urgent unmet need, which is the recognition that NASH is a real disease; that it can be present and progress with no symptoms; and that it can lead to complications. And so, you know traditionally or typically patients will have very modest elevations of their liver tests. Sometimes, it can be normal in NASH – we don’t know why some are more elevated than others. But in the past, and probably even today, some physicians will see that modest elevation in the liver tests and tell the patient “don’t worry, your other tests are normal, let’s keep an eye on it, let’s keep an eye on it”. And while it’s certainly never urgent that one investigates a modest elevation of AST or ALT which are the main liver tests, still one should not lose sight of the prospect that they could be a harbinger of more serious underlying liver disease. And so, we have a lot of work to do just to educate the providers to suspect NASH in a patient either who has a modest elevation of ALT or AST that’s otherwise unexplained, meaning they don’t have any hepatotoxic drugs, they don’t have any evidence of viral infections.  We need to educate them to take notice of that. Also, very commonly, patients come to the attention of the liver specialist because they have an ultrasound or a CT scan of their abdomen for an unrelated reason – for vague abdominal pain and the ultrasound report returns with the presence of fat in the liver. I would emphasize that, while ultrasound is very important in diagnosing fat in the liver, it cannot diagnose and distinguish NASH from NAFLD and will not quantify or detect inflammation or fibrosis. So, if we see fat in the liver and/or if we see a modest elevation of ALT, that really needs to increasingly trigger a response on the part of the provider that “I need to not only watch this, but if it persists, I need to refer them to a specialist in GI or liver disease who’s comfortable managing it”.

In the meantime, it’s also increasingly common that a provider will see a patient with modest elevation of ALT and/or fat on ultrasound and they’ll recognize that it’s probably NASH, and they will wisely advise the patient first to consider exercise and diet to lose weight, and that’s certainly always, almost always the appropriate first advice. Unfortunately, many of us, including me, are always fighting the weight battle. It’s very hard to lose weight. It’s even harder to keep the weight off. So, the likelihood that a weight loss regimen will lead to a durable, meaning long-lasting, meaningful loss of weight is about 5% so most patients may lose weight, but it’s very hard to keep it off. And yet, the amount of weight that one needs to lose to have a benefit in NASH is really quite modest. It can be anywhere from 5 to 10 kilos. And even that alone can help reset the metabolism and start to improve NASH. So, it’s certainly appropriate to recommend weight loss and exercise as a first step, but it really needs to be part of a life plan that is durable and that could be maintained indefinitely, not just a 5,6 month or one year effort, but rather a long-term effort.

To return to my point – the biggest challenge, firstly, is to recognize the widespread prevalence of NASH, to educate the doctors who are seeing patients who are not liver doctors, initially. I mean the patients with NASH are being seen by their GPs, their primary care internist, family doctors. For women, it may be an OBGYN who serves as their primary doctor. If they’re diabetic it may be their endocrinologist. All of these specialists need to be aware of the risk that their patients have NASH, without having to wait until the patient comes to a hepatologist. Because, as much as we specialists welcome the opportunity to take care of those patients, the numbers, if you look at it, are going to be overwhelming, given the amount of liver specialists both here and in Europe. And so, we hope that we can instil some of the education to the primary doctors that I’ve mentioned – the different groups of doctors, to both diagnose and initiate weight loss.

Beyond that, I’m confident that in the not-too-distant future, we will have approved therapies, because there are probably about 60 drugs in what are called phase 2 trials. And some, around 5 to 10 they’re in phase 3 trials. And I’m confident that one or more of these will start to break through and then we’ll get to combination therapy.  Certainly, if there’s uncertainty about the stage of disease or if either the patient can’t lose weight or weight loss doesn’t really change the state of the liver, that’s going to be where the GI and liver providers are going to need to step in and understand the disease better. At the extreme, the use of bariatric surgery has certainly, while never or almost never indicated solely because of NASH, nonetheless – now, many studies have indicated that when bariatric surgery is done because of multiple comorbidities of obesity, those who have NASH almost always improve if they lose weight following the surgery. So, you know weight loss, in the conventional way or in the extreme sense, with bariatric surgery is always going to be a mainstay of therapy. But we have a long way to go in terms of implementing a standardized regimen of medications for NASH. In fact, the drugs are still in clinical trials and I am happy to talk more about some of the drugs and what the outlook is for their approval. But you know the first challenge – let me return to – is simply the concept that we need to have wider knowledge and awareness, both on the part of patients and providers. And you know, in a way it’s understandable that there are no very visible public health efforts to diagnose NASH because there’s no approved therapies and so, if there were government programs here, or in Europe or in Asia, anywhere, if there were government programs that went out and started to uncover all the potential patients with NASH, and then we have nothing to offer them, that would be very unwise in terms of the expenditure of resources and manpower. But I’m confident that once drugs or other mechanisms of therapy are approved, there will be, and should be, a public health effort to actually uncover the patients. Much as we did with hepatitis C – once we had curative therapies for hepatitis C the onus on us was to now diagnose patients if they have it, because there was treatment available that could change their lives.

Elaine Quinn

And so, who do you hope to see taking on the responsibility for raising that awareness once there are approved treatments available?

Dr Scott Friedman

To be honest, the stakeholder group that gets more engaged in detection and treatment when drugs are available are the manufacturers of those treatments. That’s one case where incentives may align once there are drugs approved and they’re the right thing for patients. The companies who have commercialised those drugs are certainly going to have a vested interest in seeing patients diagnosed. And it really will have to be partnerships of professional associations, like the American Association for the Study of Liver Diseases, the European Association for the Study of Liver and so forth aligning with public health agencies, like the CDC or the WHO. But also, with some input from the companies that are manufacturing those drugs. So, all of that will start to I would say ‘unstick’ and roll out as we have meaningful treatments to improve patients’ lives. We’re not really there yet so it’s sort of waiting at the starting blocks for a greater public health effort, once we have actionable information that can intervene in the disease.

Elaine Quinn

So great, so can you talk a little bit about the drugs that are maybe in development or that you can see on the horizon?

Dr Scott Friedman

Sure. As I mentioned there’s a lot. One of the real challenges, and there are a couple of challenges in the therapeutic realm in NASH – number one is we don’t know if every patient with NASH really has exactly the same disease and disease drivers. What we see in the microscope, of course, looks similar across patients with NASH. But maybe some patients have the predominant mechanism being type 2 diabetes and problems with Insulin signalling. Other patients maybe have a more pathogenic microbiome, yet other patients may have defects in lipid homeostasis or lipid metabolism. And unfortunately, we don’t have what I call a hierarchy of disease, meaning we don’t know what is the ‘Achilles heel’ of this disease. We know very well now, all the changes in the features, starting with the gut, the amount of food we eat going through to the liver, inflammation, fat accumulation, insulin resistance, changes in the cells. And then all of that driving the fibrosis or scarring that I talked about before. And yet, we don’t know which is the one ‘Achilles heel’ that if we were to target that specific pathway, that would really turn off the disease. And so, what you have instead is a landscape filled with targets and drugs in every step of the disease pathophysiology. And it may well be that different patient groups may require different drugs because they have different drivers.  Currently, I would say, most of the drugs that are more advanced at present are focused more on the fat and the metabolic defects, rather than the scarring. With the reasoning being that if we can turn off as I said, the spigot or the drivers of injury and inflammation, that the fibrosis will settle down. And that’s reasonable.  We have drugs that improve glucose homeostasis and insulin signalling like GP-1 receptor agonists. We have other drugs that affect hormonal and nuclear receptor signalling in hepatocytes. And then we have drugs that are anti-inflammatory that block chemokines and inflammation drugs that are trying to improve the mitochondria or the energy powerhouse of the hepatocyte. And there are some drugs that are directly antifibrotic as well. And so, all of the trials so far that have shown some promise, however are not as powerful in humans as they are in rodents or in mouse models, and while the mouse models are very important in helping define mechanisms of action, they tend to be a little over optimistic in predicting efficacy when you ultimately translate it into humans – and that may be, in part because mice that we use in the laboratory are typically inbred and in a way, they’re bred to be responsive to disease stress and to therapies. And when you get to humans who are complex, genetically, the response rate falls off. And that may well be where genomics, Whole Genome Sequencing, and Exome sequencing could really fill a vital role in defining subsets of disease that establish that, in one group of patients this target, and this drug would be more effective in another subgroup of patients. It may be a different target and group of drugs altogether. And so, as I said, it’s really early days in terms of pharmacotherapy of NASH, but I have no doubt that we will start to see incremental advances, both with single drugs and maybe with combinations because we don’t know in any given patient which of those many pathways is most critical.  We want to effectively target as many different drivers within the liver as we can to have maximum benefit. So far, combination therapy trials have not been astoundingly more effective than single drugs, but it may well be a matter of finding the right combinations as well.

Elaine Quinn

Well, it sounds like there’s a lot of great work being done at the moment. And hopefully that will translate into new effective drugs being on the market very soon, alongside more awareness and better education among physicians and the general public. Of course, it’s everybody working together then to get that message out so that the growing challenge can be tackled, and I know we’re seeing some increase in patient advocacy as well which is great. So, do you think the next five years will tell a lot?

Dr Scott Friedman

I do. Just to expand on one of your points, there are at least a couple of new advocacy groups in the sort of public arena here in the US. Fatty Liver Foundation, also the Global Liver Institute. I’m sure there are some in Europe and Ireland where you are as well. Maybe a couple of other points that are worth emphasizing. One is that I think there needs to be greater public awareness – and also we didn’t really talk about – is alcoholic liver disease, and I think it’s worth both defining and distinguishing it from non-alcoholic. So, here we’ve been talking about a disease that’s effectively defined within its name as ‘non-alcoholic’ fatty liver disease. Why do we call it that? Well because, when the disease was first being recognized as a distinct entity, liver biopsies looked an awful lot like alcoholic liver disease. And yet the patients who were biopsied said “I really don’t drink”, “I don’t drink at all, I drink minimally”. And it became increasingly clear that while their liver biopsy looked a lot like alcohol, it was clearly unrelated to alcohol – it was this ‘non-alcoholic fatty liver disease’. And there-in you know, is the history of this growing problem.

But alcohol, first-of-all, the fact that they look alike tells us that they may have a lot of the same disease drivers that are similar as well. And so, there’s a lot of effort to take the lessons that we’ve learned about understanding alcoholic liver disease and see if they can translate over to understanding the pathogenesis and the treatment targets for non-alcoholic fatty liver disease. In fact, they’re so similar that there is an effort within the field – which has not really gotten full traction yet – to rename these diseases as metabolic associated liver disease, whether it’s from alcohol or from obesity. I’m not a big fan of changing the name yet for a variety of reasons, but it does speak to the idea that they’re quite aligned. But it also means that patients who have a diagnosis of NAFLD should be very prudent about their alcohol intake because you’re adding fuel to the fire. If you already have underlying liver disease as a result of obesity associated with type 2 diabetes, then it would be imprudent to drink heavily and amplify the same kinds of injury that were already been created by the obesity. And so, there are a lot of patients who probably have a combination of non-alcoholic and alcoholic fatty liver disease if they drink to excess. I think for those who’ve been diagnosed with NAFLD, it would be prudent to cut back or try to restrain from alcohol ingestion altogether.

Elaine Quinn

And finally, what are you focused on yourself then these days workwise? I know you’re heavily involved in research but are you involved much in clinical work at the moment?

Dr Scott Friedman

I’ve cut back drastically on my clinical activities although I’m going to go back on the wards in the next month, because I took on a lot of administrative and leadership roles, both within my institution and previously for our National Association. But my passion, more than anything, still remains understanding and treating fibrotic liver disease. At the basic laboratory level, we’re still trying to understand the continuing mysteries of the hepatic stellate cell and what the targets might be that turn it on or off or regulate its gene expression. And at the translational side, we do a lot of animal modelling where we work with drug companies and pharmaceutical and biotech companies to test promising compounds in a mouse model of NASH. And then I spend a fair bit of time talking to companies advising them about what kind of targets they might think about for their drugs, how they might design their clinical trials. So, you know to harken back to my starting days, if you had told me that I would be doing this some 35 years later I would have said, I don’t think I’ll be that lucky. But you know as a physician scientist, it’s always about improving the lives of our patients and for me that remains as compelling a motivation to continue doing what I’m doing as it ever was from the very beginning. And I’m living the dream in terms of what I hoped to be doing as a physician scientist. I’ve been very, very lucky.

Elaine Quinn

What a great way to finish Dr Friedman. That’s wonderful and I look forward to keeping track of your great work and hopefully we’ll see some further advances in the near future. Thank you, thank you so much for your time today.

Dr Scott Friedman

My pleasure. I’m sure we’ll have lots to talk about in the coming years.

Hosts

Elaine Quinn
Senior Education Specialist
Genuity Science

Guests

Dr Scott Friedman
Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases
Icahn School of Medicine in Mount Sinai in New York City