Paul Kwo, MD, on the Changing Face of Liver Disease

Dr Kwo focused his David Sun Lecture at the ACG Postgraduate Course on the increasing burden of metabolic-associated fatty liver disease and the need to step up efforts to increase access to effective treatments now available for patients with hepatitis B and C. 

Paul Kwo, MD, is professor of Medicine and Director of Hepatology at the Stanford University.

TRANSCRIPT:

Hi, I'm Dr. Paul Kwo, and I am Professor of Medicine and Director of Hepatology at Stanford University. I'm pleased to be coming from the annual American College of Gastroenterology meeting in beautiful Vancouver, British Columbia and I'd like to share some of the insights that we discussed today at the American College of Gastroenterology regarding the future of liver disease and how we're going to approach this broad category of patients. Most importantly, right now we have basically four pools of patients. We have patients who have viral hepatitis B and C. We have patients who have alcohol-associated liver disease and those who have metabolic dysfunction-associated steatotic liver disease or MASLD, formerly known as NAFLD. And it is this MASLD population that is going to be the largest burden of liver disease patients that we're going to be caring for for the next several decades.

The nomenclature has recently been revised. This was a multi society international process and it was an effort to standardize nomenclature and remove some of the stigma associated with our prior terminology including non-alcoholic fatty liver disease. So now we call steatotic liver disease and we divide steatotic liver disease into two main categories. We have the metabolic dysfunction-associated steatotic liver disease or MASLD, and then we have alcohol-associated liver disease or ALD. Now importantly, we now have other gradients where we combine metabolic liver disease, alcohol-associated liver disease, it's called MetALD. And depending on the amount of alcohol that you consume, we can combine these categories now and categorize people as having liver disease that's steatosis related and is related to a combination of risk factors.

In addition, we used to call the steatohepatitis with fibrosis NASH or non-alcoholic steatohepatitis. It's now MASH, which is metabolic dysfunction-associated steatohepatitis. And again, it's going to take us all a little bit of time to get used to this, but we will adapt to this. The way we evaluate these individuals is going to evolve over time. Typically now we see these individuals, we try and assess fibrosis, and we then try and biopsy those individuals who we think may have advanced fibrosis. And we do this using a variety of straightforward markers, including FIB-4, as well as elastography techniques and other proprietary serum markers of fibrosis.

Happily now, there have been multiple groups working on validating biomarkers, and it appears right now that there are three biomarkers that have been pre-qualified and cleared stage one of a qualification process. These are the NIS4, the ELF score, and the Fibrometer VCTE score. And all of these biomarkers for advanced fibrosis seem to perform better than FIB-4 and are going to move forward with further validation. And why this is important is because we should be able to validate biomarkers that allow us to establish that someone has actionable fibrotic, non-alcoholic fatty liver disease or metabolic dysfunction-associated steatotic liver disease that requires treatment and we can do this without a liver biopsy. Very important.

In addition, post pandemic, we've seen a marked increase in alcoholic hepatitis, but alcohol consumption, alcohol-associated liver disease has been problematic now for the last several years and most recently, alcohol-associated liver disease or alcoholic hepatitis is refractory to medical therapy, has become the leading indication for listing for liver transplant for men. It's number two for females and in some centers this can be a substantial proportion of the transplants we perform.

We need to be able to standardize and recognize these individuals and moving forward an important unmet need will be to identify biomarkers that can pick up early alcohol use disorder, earlier and moderate alcoholic hepatitis, as well as identifying those to be at risk for progressive hepatic disease if they continue their heavy alcohol consumption. Regarding liver transplantation right now, a lot of centers in the United States have limited sobriety pathways. In one particular publication of a hundred transplant centers that were surveyed, 85% had limited sobriety pathways. We need to make sure that we have national standards for how we approach individuals who are transplanted in a limited sobriety pathway.

Just like we have standards for transplant for hepatocellular carcinoma, where we have certain standards to diagnose hepatocellular carcinoma and how we survey them afterwards and we track centers' quality and making sure that they're transplanting appropriate candidates, we are going to need the same standards for those who undergo transplant for a limited sobriety pathway given that transplantation is a limited resource. This will mean not only standardizing the criteria for listing for transplantation, but making sure that all centers have harm reduction programs, centers track their survivals and graft outcomes, as well as patient outcomes. And in addition, also come up with methods for harm reduction post-transplant to ensure that the grafts in the patients perform well post liver transplantation.

Dr. Paul Kwo:

We will need to move forward in our efforts to eliminate viral hepatitis worldwide.

The Centers for Disease Control back in 2015 laid out an ambitious agenda where they said they wanted a 90% reduction in new cases of hepatitis as well as a two-thirds reduction in mortality from viral hepatitis B and C. Unfortunately, the COVID pandemic somewhat derailed these efforts, but we're now re-engaging, and it will be important as we move forward now to incorporate what we've learned from the pandemic in our efforts to eradicate viral hepatitis.

Particularly with viral hepatitis B, we have excellent suppressive therapies for hepatitis B now, and we need to improve upon and simplify our treatment guidances. All of the societies have released treatment guidances, and they're well-written, they're based on rigorous data, and they involve treatment thresholds that include ALT levels and viral levels. Unfortunately, they are still quite complex, and there are still categories of patients who wind up in the so-called gray zone.

When these individuals are followed by experienced hepatologists, they do very well and the outcomes are excellent, but the vast majority of people with hepatitis B in the US and worldwide are not under the care of hepatologists, and therefore we need to simplify our treatment guidances to make sure that all individuals can be appropriately followed and can be placed on suppressive therapy as we pursue curative, that is, achieving functional cure, therapies for hepatitis B.

Indeed, there have been a few recent guidances that have simplified treatment down to simply age plus a viral level. As we move forward, I think more of these guidances will be released. It's certainly happening in Asia, and we are seeing more of these guidances in the US. We eagerly look forward to the WHO guidance, which should be released shortly.

Hepatitis C is a disease that we have a curative therapy for, and hepatitis C is very easy to cure. It's much more challenging to eliminate. We need to decentralize our hepatitis C care. That is, we need to bring hepatitis C care to where patients are. The opioid epidemic unfortunately has led to an increase in hepatitis C cases, and when patients seek care for their opioid use disorder, we need to be able to provide point-of-care testing, identify those who have active hepatitis C, and offer treatment right then, that is a test and treat model.

There are more of these that are now being established, and primary care providers are going to need to play a primary role in the treatment of hepatitis C. Just like primary care providers now treat Helicobacter pylori, they should be able to treat hepatitis C, and we have multiple avenues, particularly with the use of digital health such as echo programs, available to help train primary care providers. What would be a real game changer is if we could develop an effective vaccine for hepatitis C. Thus far, these efforts have not been successful, but if we can develop an effective vaccine, that too would improve greatly our hepatitis C elimination efforts...

Worldwide. But in 10 to 15 years, it would be great if we can eliminate these as public health threats. Monogenic diseases are going to be treated differently moving forward, and again, artificial intelligence is going to play a role in our practice. It will be, though, a technology that complements our practice, and we still must recognize that it will be physicians who will still be primarily caring for our patients. It's been a great meeting, and I hope to see you at a future meeting. Thank you so much.

We also have a growing burden of hepatocellular carcinoma. It was interesting. Two recent reports looking at our CR data suggested that the rate of HCC has maybe declined slightly in the United States, but unfortunately not all groups benefited from this. We didn't see reductions in non-Hispanic blacks and American Indians and Native Americans, Alaska, or, excuse me, native Indians and Alaskan natives also did not share this benefit. One of the concerns regarding the future burden of hepatocellular carcinoma is our growing burden of those with metabolic dysfunction-associated liver disease, or MASLD.

One of the most concerning aspects of this is that about one-third of all HCCs associated with MASLD occur in the absence of cirrhosis. We currently screen individuals for hepatocellular carcinoma and hepatocirrhosis. That's what the most recent practice guidances have told us. But again, just like hepatitis B, MASLD is associated with a substantial cancer risk and those without cirrhosis, and why that's important is because MASLD is going to be the dominant liver disease that we're going to have to contend with.

Therefore, we're going to need good biomarkers that we can utilize to identify these individuals at risk and identify these individuals through a blood test rather than trying to do ultrasounds on individuals with MASLD, which, again, currently is one quarter of the world's population. It won't be practical to do ultrasounds every six months on these individuals, and biomarker risk stratification will hopefully provide some solutions to reduce this risk.

The future of hepatology is really quite bright. We are going to have to learn to treat a large steatotic patient population, but we are acquiring the tools to be able to address these individuals. In the meantime, for viral hepatitis B and C, we hope that we'll continue our elimination efforts not only here in British Columbia, in the US, and worldwide, but in 10 to 15 years, it would be great if we can eliminate these as public health threats.