Thursday, September 19, 2024 | New York Academy of Medicine (NYAM)
1216 5th Ave, New York, NY 10029
Dr. Andrea D. Branch, PhD, highlights the use of low-dose CT screening to detect liver steatosis, which can serve as an imaging biomarker for metabolic syndrome. She discusses the development of algorithms for automatic detection and the importance of reporting steatosis in radiology scans. Branch also introduces the concept of metabolic dysfunction associated with Steatotic liver disease (MASL-D) and the potential impact of new drugs targeting metabolic disorders.
Watch Dr. Andrea Branch's Presentation Below:
See Dr. Andrea Branch's Slides Below:
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Transcript of Dr. Andrea Branch's Presentation:
(0:00 - 0:09)
Andrea. Thanks so much, Mort. It's been fun working with you, and thanks to David and Claudia.
(0:10 - 1:02)
You've just been fantastic collaborators, and I love working with you. So, talking about opportunities for low-dose CT screening for detecting fatty liver, which is liver steatosis, and this is a feature of fatty liver disease, and I think it's also a potential imaging biomarker of metabolic syndrome, which I know has been a controversial topic over the years, but I think, especially now that we have drugs that can really target obesity and some of the components of metabolic syndrome, it's really time to start thinking about whether we should be looking for imaging biomarkers of patients who are going to be able to benefit from drugs that directly target metabolic disorders in a new way. So, I have nothing of interest to disclose.
(1:03 - 3:47)
This is a histology slide. It illustrates what liver steatosis is, those big white globs, that's fat in the liver. Also important in the slide, blue shows fibrosis, which is the feature in the liver that's really associated with liver-related outcomes, and also inflammation, which are the smaller purple cells.
So, steatosis is this one feature of steatosis, fibrosis, and inflammation. Steatosis is the one component that can be identified in low-dose CT scans, and the reason for that is because fat in the liver decreases the signal attenuation and allows moderate to severe steatosis to be identified. Moderate to severe steatosis is defined as macrovesicular lipid droplets in 30 percent or more of the hepatocytes, and this equates to a fat fraction defined by MRI of about 17 percent.
So, a Hounsfeld threshold of about 40 units is often used to diagnose moderate to severe steatosis, and this threshold was identified through a series of studies in which CT scans were compared to histology data. Oh, I don't know why, sorry about that, but Artit and Tony, in collaboration with Claudia and David and others here, developed a computer algorithm that allows us to automatically detect liver steatosis, and the algorithm works very well. It really gives the same value that you have if you manually review the CT scan.
This is just one of a number of algorithms that are coming forward that allow moderate to severe steatosis to be automatically identified in CT images, and I think Mark may be speaking about some of the work from his group later. So, if you have steatosis and you have a cardiometabolic risk factor, you have a disease called metabolic dysfunction associated steatotic liver disease, or MASL-D. This is the new replacement term for NAFLD, non-alcoholic steatohepatitis, and I've shown the diagnostic algorithm that was worked out through a modified Delphi project to identify a new term.
(3:48 - 12:30)
At the right side, you have the particular cardiometabolic risk factors of obesity, type 2 diabetes, hypertension, high triglycerides, and low LDL. So, if you have steatosis in one of those, you have MASL-D if you have no other risk factor for liver disease, to explain the findings. So, it's very common.
About 38 percent of U.S. adults have steatosis, and about 33 percent, or the vast majority, have this condition called MASL-D. So, it is 33 percent, but that still leaves 5 percent of people with steatosis who have some other liver disease, and it often is associated with alcohol because, like metabolic syndrome, alcohol also increases the fat content in the liver. So, it's important to report steatosis when you see it in a radiology scan because it could lead to a diagnosis of MASL-D, or alcohol-related liver disease, and also because it could be an indication of metabolic syndrome.
And now that we have GLP-1 receptor agonists and trizepatide, which includes a GIP agonist, we really have drugs now that can target metabolic dysfunction in a way that's bringing meaningful benefit to patients. So, I've shown here some data from the New England Journal. If you want a high-impact publication, I would say it's a good idea to be testing these new GLP-1 receptor agonists on one body system or another.
So, it shows a benefit for cardiovascular endpoints, and trizepatide showed just a remarkable rate of response in patients with fatty liver disease of 62 percent, having a decrease in the histologic injury that's associated with fatty liver disease. So, in addition to being important because it can uncover liver disease and potentially identify metabolic syndrome, the use or the utility of finding of steatosis in MASL-D is that it could also improve risk predictions for other diseases, and in particular for type 2 diabetes. So, MASL-D really improves prediction for type 2 diabetes, as shown in this study.
So, after adjustment for all other variables, however, liver steatosis in this very large study, which used time-varying models, was not shown to be independently associated with incident cardiovascular disease, all-cause mortality, or cancer. So, I think it's important to recognize that this liver steatosis is going to have utility in prediction of some types of disease, probably more than others, especially for type 2 diabetes. So, MASL-D is extremely prevalent, as I say, 33 percent of the adult population, but fortunately, it has an incredibly low case mortality rate or case fatality rate.
So, in this study, my student, Ning Ma, took data from the National Health and Nutrition Examination Study, NHANES, and we looked at all-cause mortality for MASL-D versus people with no liver steatosis and absolutely no indication of any liver disease at all, and mortality was the same with over 20 years of follow-up in NHANES. What does increase mortality is alcohol and viral hepatitis. So, again, despite its enormous prevalence, and it's often heavily covered in journalism, MASL-D only accounts for about 8 to 12 percent of all liver-related deaths.
Most liver-related deaths in the United States are due to alcohol. So, I kind of lined up these graphs, and I put in the blue line there to make it easier to compare deaths from alcohol to deaths from MASL-D, and you can see the deaths from MASL-D, they do rise above the x-axis, but not that much, and only really for whites. If you're black, your likelihood of having a serious outcome from MASL-D is very low, and that is because blacks and African-Americans have reduced risk of liver steatosis, but they have a high risk of diabetes and some other complications of metabolic syndrome.
So, I wanted to include this because I think it really highlights the importance of looking at a variety of individual risk factors and recognizing that we're talking about complex and very heterogeneous diseases. So, this slide's just to highlight what I call the MASL-D paradox. Massive prevalence, but a benign course in many people.
The cartoon is from the Aladdin, when the genie comes out and he's complaining that he has cosmic powers, but teeny tiny living space. So, in the liver world, we're left with the need for research to determine which patients with MASL-D will have progressive disease and which will need liver-targeted therapies. Mort mentioned resmeteron was recently approved by the FDA to treat liver disease, and which patients really will have a resolution of MASL-D if they just receive treatment for their upstream metabolic syndrome and obesity and diabetes with drugs that are GLP-1 receptor agonists and their relatives.
So, I wanted to include this study partly as a headline to what Dr. McKanick and Dr. Fried are going to talk about, and it really highlights the importance of different types of adipose tissue in the body. All fat is definitely not created equal. So, this is a study of a PPAR-gamma receptor agonist, and in this study, the people on pioglitazone are shown in red, and I've tried to indicate increase.
So, this drug causes an increase in body weight, which made it extremely unpopular with patients and providers alike, because we're dealing with a patient population that already has weight as a problem, but I think it's very interesting that, yes, body weight increased, but there was also a change in the subcutaneous fat, and then down on the bottom, there's a decrease in visceral fat, and this was accompanied by a decrease in liver fat. So, it just goes to highlight that adipose tissue redistribution is accompanied by a loss of liver fat despite an increase in weight, and this really highlights the importance of understanding different types of fat depots in the body and the extent to which we might be able to examine this using imaging data. Are you looking at me because of time? I'm over time.
So, just to quickly emphasize some of the risks and harms that we can talk about, part of the discussion, just kind of my bottom line, that I think this is going to be an imaging biomarker of metabolic syndrome, potentially useful as a predictor of diabetes, finding alcohol. The fact that we can have serial data will help us better define the natural history and look at interactions between organ systems, and I just included this slide. I won't go into it because of the time, but I can tell you that what it shows is that the AGA, the American College of Gastroenterologists, have identified steatosis as a very common incidental finding, and there's an entire algorithm that's already in place for working it up, and we've hardwired the Epic record at Mount Sinai to make it very easy to follow up by doing a non-invasive test for liver fibrosis, and I just want to thank you and thank all the members of the team.
The presentations were hosted by I-ELCAP – The International Early Lung Cancer Action Program.
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