Episode 49: Nonalcoholic Liver Disease

Karie Dozer [00:00:04] I'm Karie Dozer and this is TGen Talks. Today we're talking about non-alcoholic fatty liver disease, a condition that probably doesn't sound familiar to most Americans, but one that is probably far more prevalent than most of us realize. The condition causes excess fat in one's liver cells, and it covers a wide range of liver conditions. Our guest will talk about why this disease might be due for a name change and why it varies widely in the way people experience it. Factors like genetics, lifestyle, diet, gender and even stage in life can mean everything for those who learn they have it. And for this episode of TGen Talks, I'm joined by Dr. Johanna DiStefano. Tell me your title, what you do at TGen, and tell me what you study. What's your job?

Dr. Johanna DiStefano [00:00:53] My title is Professor and I'm the head of the Diabetes and Fibrotic Disease Research Unit at TGen. What I'm focused on is the role that the liver plays in mediating the body's response to the environment in metabolic disease that develops in the liver. I started off my career studying type two diabetes. And Type two diabetes is, you know, is a raging epidemic and it's accompanied by obesity. About 15 years ago or so, I started becoming aware of the role of the liver in all of this metabolic mess and how the liver really responds to the diet. For example, a diet high in ultra-processed food and the liver is going to take on fat because the body doesn't have anywhere else to put the fat. And then when the when the liver starts taking on fat, then we see insulin resistance developing. So we used to think that maybe diabetes caused fatty liver disease, but now there's a possibility that fatty liver disease is indeed causing diabetes. So it's a bi directional relationship.

Karie Dozer [00:02:01] Do they always happen together?

Dr. Johanna DiStefano [00:02:02] Not always.

Karie Dozer [00:02:03] Okay. So you study something called nonalcoholic fatty liver disease. It's a long title, but it seems pretty straightforward. Is it just as simple as it sounds?

Dr. Johanna DiStefano [00:02:13] So first of all, nonalcoholic fatty liver disease is a really awful name for a disease. You know, first of all, it has this stigma associated with alcohol. And second of all, it's just it doesn't roll off the tongue very well. Right. Some people have proposed renaming it to metabolic fatty liver disease.

Karie Dozer [00:02:30] That's not much better. 

Dr. Johanna DiStefano [00:02:31] It's not, is it? And besides, it implies that there's a metabolic defect, but a lot of people develop fatty liver disease without changes in metabolism. And I like to think of that as like there's many paths up the mountain, but the view at the top is the same. So you can still get in the fatty liver, but you're getting there in different ways. Some of it could be lifestyle, some of it could be genetic susceptibility. Some could be, you know, alcohol intake.

Karie Dozer [00:03:00] But once you have that fatty liver, do you always or most always develop type two diabetes?

Dr. Johanna DiStefano [00:03:06] No, but a significant proportion of people do.

Karie Dozer [00:03:10] So that's what we're trying to get at, trying to get at the type two diabetic. So the name nonalcoholic fatty liver disease distinguishes itself from alcoholic, fatty liver disease. Tell me about the difference in the extremes in those two.

Dr. Johanna DiStefano [00:03:24] This is a good question. It's never as cut and dried as you think it would be in order for you to say with confidence that alcohol is not contributing to the development of fatty liver and an individual. The only way that you can really do that, excuse me, is to know that the person doesn't really drink at all, because we are just starting to realize that different people have different tolerances or different sensitivities to alcohol. So you could have a glass of wine with dinner three times a week and you might think that's fine. But maybe because of different factors your genetics, you know, your lifestyle, whether you and you have a poor quality diet. On top of that, you could develop an abnormal hepatic response to that small amount of alcohol because of the extenuating circumstances. And then, you know, someone else could theoretically be able to, you know, drink a couple of drinks a day and be fine.

Karie Dozer [00:04:20] I think most people listening would say, I know both of those people. You I know the person who didn't seem to drink at all yet died of something alcohol related. And I know my great uncle who, you know, drank until he was 95 and nobody knew how he did it. Is that just boil down to their genetic makeup?

Dr. Johanna DiStefano [00:04:38] No, I don't think it's just genetics. I think it's a confluence of different things. It could be genetics, it could be lifestyle factors. You know, it could be your gender. It could be your stage in life. For example, if you're a woman and you're after menopause, your risk is higher. 

Karie Dozer [00:04:57] So there's the alcohol caused or at least we've touched on it a little bit, the nonalcoholic. Fatty liver disease you said has a has a great genetic component. So some people just are dealt a poor hand in that area. Who is dealt a poor hand and who has a better a better chance at not developing this?

Dr. Johanna DiStefano [00:05:15] That's a great question. So the genetic variants that are most associated with the development of fatty liver are in a gene copy PNG play three and this was identified out of Texas in Helen Hobbs Group. It was a really great genetic study and the results of that study seem to indicate that people of Hispanic ancestry are more at risk from variance in this gene than other populations. And indeed, we know that when we look at the prevalence of fatty liver disease, nonalcoholic fatty liver disease, that we see that individuals of Latino ancestry have a higher prevalence than people of Caucasian, whereas people of African ancestry are at the other end of the spectrum. We don't see as much fatty liver in people of African ancestry, even given the same amount of body weight.

Karie Dozer [00:06:11] Given that information, what does somebody do if they know they have a genetic predisposition? Is it simply the way they live?

Dr. Johanna DiStefano [00:06:18] Yes. Like if you knew that you had this variant, then you would want to be very careful of your fat intake because these variants seem to affect the release of fat from the liver. If the fat can't effectively get rid of triglycerides from the liver, then they're going to accumulate. Right? And so a lot of these variants really affect the export of fat from the liver. 

Karie Dozer [00:06:43] So if that's something that is preventable, but at least it's addressable, how available is that information is one of your goals to get to the point where everyone has that information? And how close are we to knowing really what kind of hand we've been dealt?

Dr. Johanna DiStefano [00:07:00] Oh, this is the crux of the matter. Hepatologist are doctors and specialists who study the liver, who study liver disease. So outside of the field of hepatology, not many, not many clinicians are aware of the significance of nonalcoholic fatty liver disease. Primary care physicians are at the forefront, and they're going to be the ones who are going to identify nonalcoholic fatty liver disease. But many people don't even know about it. And usually people get diagnosed, incidentally, because there's no symptoms. You know, they're usually getting some initial ultrasound for something else or they're getting bloodwork for something else. And it turns out that, oh, hey, there's a lot of fat in the liver or, hey, the liver, enzyme levels are high. What's up with that? But they're not really equipped to deal with this. And unfortunately now, no, call it fatty liver disease is burgeoning. Yeah. You know, the rates are galloping.

Karie Dozer [00:08:01] What about the American diet? If you take alcohol out of the picture, Americans eat much differently than we did 100 years ago. 200 years ago. What is the food that we eat predominantly in this country due to that metabolism and the ability of our liver to take care of alcohol?

Dr. Johanna DiStefano [00:08:20] So some people call the food industry in our country, you know, big food. And there's a lot wrong with big food. And even worse, you know, we give this food to our children when they're growing up like cereal or, you know, you think about the marketing toward children and children want to eat that. Well, that's where our eating habits develop in childhood, and it's very hard to undo those as an adult. So the eating habits you develop in childhood are usually the same ones you have as an adult. There is so much wrong with the food that we eat. Sad, even food really. And then there's just so much sugar. Now the big food is getting away from putting sugar and stuff because, you know, they want to make money and people are getting wise. So people don't want to buy products with sugar. So big foods pulling sugar out of products, which is a good thing. But then, you know, they're also putting other stuff in.

Karie Dozer [00:09:15] A lot of other things in the food besides sugar. 

Dr. Johanna DiStefano [00:09:17] Right? Right.

Karie Dozer [00:09:19] So tell me about your lab. Tell me about your work and what it is that you're trying to do to address all of these problems. It seems like a lot to do.

Dr. Johanna DiStefano [00:09:26] It is it's allowed to do. And unfortunately, there's a lot of brilliant minds in this space who are working on this problem. So, you know, my hope is that we'll get there sooner rather than later. Some of the work that we're doing now, we're looking at genetic variants in normal weight people. So let me backtrack a second and say that, you know, the Darwin used to be that fatty, nonalcoholic, fatty liver disease developed in people who had obesity or who were overweight. And we're finding out that that's actually not true. You know, nonalcoholic fatty liver disease in lean people is actually increasing. And so that kind of throws the. The whole idea of, you know, the role of obesity out the window. Still, people who have obesity are more likely to get nonalcoholic fatty liver disease than normal people. So in normal weight individuals, we think that when nonalcoholic fatty liver disease develops, it's more likely to develop because of genetic susceptibility and also lifestyle factors. And that would be a sedentary lifestyle. That would be a poor quality diet. And some of these genetic variants, for example, there's variants in your gene that is the only gene in the body that produces a nutrient called choline. Cooling is an essential nutrient, and if you have those variants, you're not producing calling. So if you have a calling deficient diet, you will develop fatty liver disease. And so we know we're starting to learn more and more about this. So what my group is really focused on is the genetic factors that influence the development of nonalcoholic fatty liver disease and lean people and try to raise awareness of nonalcoholic fatty liver disease in this population among clinicians. In addition to that, we also see an increase in nonalcoholic fatty liver disease in postmenopausal women. So we're doing work in that space, too.

Karie Dozer [00:11:20] Tell me about your lab. Tell me about your team. And what is the question that you would you set out to answer every day?

Dr. Johanna DiStefano [00:11:27] So the overarching question that we're trying to answer is how does nonalcoholic fatty liver disease develop? How does the liver communicate with other cells in the body, other organs in the body? We are primarily interested in identifying better ways to detect fatty liver disease. For now, the gold standard is liver biopsy. And of course, it's invasive. It is, and it's not very accurate. And so eat less tigerfish is a better approach in that sense that that's a measure of the stiffness of the liver. So what we're also interested in then looking for targets because there are no approved therapeutics for the treatment of fatty liver disease. And finally, it's really also looking at the different ways that the disease develops. So if you're developing a fatty liver because of underlying insulin resistance, you're going to be you're going to be more effectively treated with a pharmaceutical that's going to improve insulin sensitivity, whereas if you're developing fatty liver because of a genetic mutation, then you're going to need a different approach.

Karie Dozer [00:12:40] Yeah, it's back to what you said about the view. At the top of the mountain is the same, even though all of those journeys might look very different. Right? Yeah. All of those patients are winding up in the same place.

Dr. Johanna DiStefano [00:12:50] Right.

Karie Dozer [00:12:51] So how hopeful are you that in the next 10 to 20 years there is significant progress made? Because you did allude to the fact that clinicians aren't always aware. The people studying this issue like yourself, it's not a large group.

Dr. Johanna DiStefano [00:13:06] Mm hmm. 

Karie Dozer [00:13:07] What's your hope?

Dr. Johanna DiStefano [00:13:08] Well, I'm very confident that we're getting there. I feel like we're having an escalation of data coming out. There's some very good work going on within the microbiome community showing the influence of gut dysbiosis. That means having an altered composition of gut bacteria. Also, we're seeing some results with some drugs, you know, drugs used in the treatment of type two diabetes that might have a positive benefit on fatty liver disease.

Karie Dozer [00:13:36] For the audience for this podcast, what would you like them to know most about what it is that you're studying?

Dr. Johanna DiStefano [00:13:42] That fatty liver disease isn't your fault. You know, there's so many things out there that are conspiring to put fat in your liver. It's not your fault.

Karie Dozer [00:13:51] That's a hopeful way to end the podcast. I appreciate it. Thank you so much for your time.

Dr. Johanna DiStefano [00:13:55] You're welcome. Thank you for having me.

Karie Dozer [00:13:58] For more on TGen’s research, go to TGen dot org slash news. The Translational Genomics Research Institute, part of City of Hope, is an Arizona based nonprofit medical research institution dedicated to conducting groundbreaking research with life changing results. You can find more of these podcasts at TGen dot org slash TGen Talks, Apple, Spotify and most podcast platforms. For TGen Talks, I'm Karie Dozer.