Interview with Prof. Scott Friedam in the APASL2009

Hepatology Digest: I’m here at APASL 2009 with Professor Scott Friedman, it’s an honor to interview you today Professor Friedman.  Thank you for joining us.

Pro. Friedman: My pleasure.

Hepatology Digest: First question I have for you today, obviously with a memorandum of understanding between AASLD and APASL, there’s going to be some cooperation, can you talk a little about that cooperation, what form it will take and what you hope to achieve.

Pro. Friedman: Well first of all, we’re delighted at the opportunity to partner officially with APASL.  This is a vital part of the world particularly with respect to liver disease.  Many new treatments are being pioneered here, many new approaches and of course the prevalence of liver disease in the Asian Pacific and in particular hepatocellular carcinoma are larger than they are in the United States.  So in many ways we need to learn from our Asian colleagues.  The memorandum of understanding is really an effort to align our interests, to create synergies between the two associations in whatever form that might take; including joint programming and conferences, joint efforts in lobbying for funding from government agencies, and greater awareness of liver disease in terms of screening, and also trying to develop new treatments together possibly including joint clinical trials.  So we are very open minded about how this memorandum of understanding will be realized over the subsequent years, and that’s really for each of the associations to develop as they see fit.  But it really solidifies our relationship officially so that we can embark upon joint projects that ultimately will accelerate the development of drugs and improve the health of our patients, both in the United States as well as of course the Asia Pacific region.

Hepatology Digest: I’m curious, obviously as a Chinese journal, we’re really interested in your views on that.  You mentioned a lot of the new innovations and things coming out of Asia Pacific.  How about China specifically, how about the recent developments and contributions from researchers and clinicians in China?

Pro. Friedman: Well of course China represents the largest concentration of both patients but also expertise in chronic liver disease anywhere in the world.  And so we are working as much as possible with Chinese physicians to understand the Asian approach to managing liver disease also keeping an open mind about herbal and traditional Chinese medicines, but most importantly, really borrowing expertise because in many ways the Chinese experience is about 10 years ahead of what we’re seeing in the United States in terms of levels of chronic liver disease and the risk of hepatocellular carcinoma.  And so we really have a lot to learn from China in terms of their approach and of course the growth in China, technologically and scientifically, is absolutely staggering.  We’re really quite excited about partnering with China in particular, to learn more about their approaches and of course share our ideas and develop programs together to accelerate advances.

Hepatology Digest: I’m curious, obviously with some of the changes going on especially in China, people getting wealthier and its life changing.  How about the incidences of non-alcoholic fatty liver disease?  You talk about how is it ten years, and how is that the experience that’s happening in Asia Pacific and China, how does that mirror what perhaps happened in the US and other western countries?  Are their experiences similar in what’s happening?  Are they following a similar trend in that case?

Pro. Friedman: Yes, its a very important point.  So in many ways unlike the viral hepatitis paradigm we are ahead of China, but for all the wrong reasons if you will because of the prevalence of obesity and metabolic syndrome is greater and is accelerating faster in the west than it has been in China.  Having said that, the change in the diet and the activity of Chinese and Asians in general and the prevalence of obesity is also increasing in Asia, perhaps most importantly, it seems as though Asian populations are at more risk for metabolic liver disease and fatty liver at lower levels of increases in their body mass index than in the west.  So where as we are looking to patients who are of a body mass index of greater than 25 before we’re concerned about the prevalence of NASH (nonalcoholic steatohepatitis), in Asians, particularly South Asians but also in East Asians the development of fatty liver and NASH can occur at much lower levels of obesity.  Of course the Chinese and the Asia Pacific region are grappling with this just as we are because we’re still learning about the natural history of the disease, the risk of inflammation and fibrosis, and of course better more sensitive and more accurate tests for both diagnosing but also newer approaches to treatment.  So we’re really in the early stages of this epidemic and again, sadly, we have – meaning the west – Western Europe and the United States, are grappling with obesity to a greater extent but the expression of this disease in Asian populations may be a little different.  We will learn from each other in terms of the genetic and ethnic factors that may influence this disease.

Hepatology Digest: And you just mentioned fibrosis, the understanding of hepatic fibrosis, or the liver’s scarring response, has emerged as a major focus of current research in hepatology.  Could you please talk about a little bit of the progress in these fields?

Pro. Friedman: Progress of fibrosis has really been astonishing over the last ten to twenty years.  I’m old enough to remember that twenty years ago the dogma was that once you had scarring on the liver, it would simply get worse.  In part that’s because we had no way to treat the underlying liver disease that led to that scarring.  One of the most important series of observations that have emerged in the last ten to five years is now that we have effective treatments for viral hepatitis, both clearance of Hepatitis C and long term suppression of Hepatitis B, we begun to appreciate that the liver has an incredible capacity to resorb scar.  There is a large amount of evidence, both in Hepatitis C and B, that if you control or eradicate the viral infection much of the scar will resorb, even in patients who are cirrhotic.  That has really led to a completely different appreciation for the dynamic nature of fibrosis, not only in its ability to develop in patients who have chronic liver disease but also in its ability to regress in those in whom we can suppress the underlying liver disease.  Trying to understand or understanding the mechanisms by which the liver naturally resorbs scar really creates opportunities to exploit those pathways in the form of therapies that will regress scar even when the underlying liver disease is persistent, for example viral hepatitis or fatty liver disease.  So with that new understanding of mechanisms of regression, we’re really at a point now where we’re beginning to develop meaningful therapies, certainly in animal models.  We hope over the next five years, in good clinical trials, that we will really establish that we can treat the fibrosis without affecting the underlying liver disease and still anticipate improvement in fibrosis, prolongation of health, and ultimately decrease mortality and complications.

Hepatology Digest: You mentioned on the treatment side, how about on the imaging side of diagnostics.  I know it seems some of the non-invasive methods, FibroScan and such have helped.  How do you forsee we will be able to use these non-invasive methods.  When will we really be able to tell between very close stages of fibrosis because obviously now it’s not really there.  Can you talk about that?

Pro. Friedman: Well I think that’s a fair point.  Before we get to new modalities of diagnosis I think it’s fair to acknowledge that liver biopsy is not an ideal test.  It’s certainly very invasive, we’re only sampling about one fifty-thousandth (1/50 000) of the liver and so there is some sampling variability among different regions of the liver.  It does not really tell us anything about the function of the liver or the rate of change of scar accumulation or regression and of course we can only go biopsy along long intervals – maybe a year or two at the most, and even then it is probably being somewhat aggressive.  So that has really set the stage for us to take a completely new evaluation of how we assess not just scar formation but the integrity and the metabolic reserve of the liver.  Some of those advances are in fact coming with things like FibroScan and serum markers, but there’s a whole new generation of tests that are under development that assess liver blood flow, metabolic reserve, and overall integrity of the liver in a way that really is complimentary to the biopsy.  In other words, tests that will measure the functional reserve of the liver as an indication of when the patient is beginning to accrue risk of liver failure as well as non-invasive method that ultimately will assess the portal gradient and other measures of liver function but also the likelihood of liver decompensation.  So I would say that we’re really just turning the corner now in appreciating both the limitations of biopsy on the one hand, and the many complimentary ways we can assess the status of the liver and the likelihood of decompensation going forward.  I think it’s such a tremendously exciting time.

Hepatology Digest: And one final question for you today, this is regarding cirrhosis.  Obviously the link between cirrhosis and HCC (Hepatocellular carcinoma) is a real concern.  What can we do to prevent those patients who have cirrhosis from developing HCC?

Pro. Friedman: That remains one of the great mysteries of our field.  And that is that it’s well established that certainly in Hepatitis C, patients really aren’t even at risk for hepatocellular carcinoma until they’re cirrhotic.  In Hep B we recognize that patients are at risk at any point in their disease although good viral suppression of Hep B will reduce greatly the risk not only of cirrhosis but of hepatocellular carcinoma.  But to return to the fundamental issue, we have no understanding of why the cirrhotic liver is so permissive for the emergence of cancer.  What is there about the scar in the liver that makes cancer so much more likely?  This really presents a new frontier for research or which we really have very few answers answers and really no practical insights.  We know from a clinical perspective that once a patient is cirrhotic we must screen them very aggressively, at least every six months for the emergence of small cancers so that therapies can be curative.  But we really have no ways of assuring or of reducing the risk of cancer once a patient is cirrhotic short of treating the underlying disease.  So if we think about it, if we can reverse cirrhosis we good antiviral therapy, then we would anticipate and in fact early data would suggest that then the risk of cancer goes down.  We’re not yet at the point where we can treat with an antifibrotic, reduce the scar, and decrease the incidence of hepatocellular carcinoma.  That really represents the next frontier, linking the mechanisms of cancer to the presence of fibrosis and then intervening in some way so we can attenuate or reduce the risk of cancer in patients who are already cirrhotic.  That’s perhaps where our trainees in the next generation can grapple with although it is certainly something I really wrestle with a lot in trying to identify the new frontiers both of research and also of clinical care.

Hepatology Digest: Once again, Professor Friedman thank you for joining us today.  It’s a great pleasure.

Pro. Friedman: The pleasure is mine.  Thank you.