Carl Maronich (Host): This is Healthy with VCU Health. I'm Carl Maronich. Twenty years ago, liver specialist Dr. Richard Sterling of Virginia Commonwealth University developed a non-invasive test to assess liver damage.

The test, called the Fibrosis-4 Index or FIB-4 Index, is a simple calculation based on simple blood tests. The FIB-4 Index has stood the test of time. It is recommended by every major gastroenterological and hepatological association in the world. It's easy for your primary care physician to calculate in the office and doesn't require any high-tech equipment. Patients who have obesity or diabetes or both, or who drink alcohol, or who have untreated viral hepatitis should talk with their physician about the FIB-4 Index. We're very fortunate to be joined by Dr. Sterling. Doctor, welcome to the podcast.

Dr. Richard Sterling: Thanks, Carl. Thanks for having me.

Host: Absolutely. And I'll also mention that Dr. Sterling is the Chief Clinical Officer of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University. So obviously, an expert on liver health. Doctor, I'll congratulate you on having developed the FIB-4 Index, which has helped so many people and will continue to do that. But let's start, if we can, by talking about how someone might know they have liver disease.

Dr. Richard Sterling: A liver disease should be suspected in anyone who has a risk for viral hepatitis, such as a history of intravenous or intranasal drug use, even if it was many, many years ago, or anyone who has high-risk sexual behaviors with multiple sex partners or unprotected sex, anyone who uses alcohol in excess, anyone with a family history of liver disease, or as you've mentioned, anyone who's overweight, obese, has type 2 diabetes, or high triglycerides.

And often, the liver disease is discovered only by a doctor getting routine liver enzymes as part of your annual checkup. And when those liver enzymes are at least 1.5 times the upper limit of normal, you should get additional testing or be referred to a specialist to figure out what's going on. Too often, a doctor sees these mildly increased abnormal liver tests and blames them on medications or something else, which may or may not be the case.

Host: And, Doctor, maybe also kind of a basic thing, but what is the overall impact on someone's health if they have liver disease?

Dr. Richard Sterling: Well, most people with chronic liver disease may die with it and not from it. But a significant portion of patients over time, the liver disease, whatever the cause is, will then lead to chronic inflammation, and that can lead to chronic scarring or fibrosis in the liver, which over time can then lead to cirrhosis, which places someone at higher risk for developing liver decompensation, for example, and needing a liver transplant or developing liver cancer.

Host: So obviously, something that needs to be taken care of. And as you mentioned, in getting tested annually, is that part of a routine exam that a patient would go through getting their liver enzymes tested?

Dr. Richard Sterling: Any patient can request the labs needed to calculate the FIB-4 when they get their routine blood work. Those include liver enzymes and a complete blood count, which includes the platelet count, and that's really all that's needed. Sometimes a physician will only order part of those. And so, you won't have all of the tests that are needed to make the calculation. And so, these are really routine tests and can be done by a primary care provider or any provider that you see and really don't need to be done by a specialist. You or the doctor can then put these three things along with your age into a very simple formula that's available on most of the medical apps that we use, or you can just look on the internet yourself, and the patient can calculate their own FIB-4. Sometimes it will be automatically calculated through the electronic health record. But if you have these tests, you can calculate the FIB-4 on your own if you need to.

Host: Interesting. You know, prior to the FIB-4 test, how were people diagnosed with liver disease?

Dr. Richard Sterling: So, I think the first thing that we do is we try to determine the cause of the underlying liver disease, and we do that by just taking a careful history and doing some routine tests because many patients may not know they have a liver disease until the test comes back. We also, as part of this then, we'll test to see if you've ever been exposed to viral hepatitis. And we might test for some more specific uncommon diseases.

If you're overweight, have type 2 diabetes or hypertension, you may be at risk for what we call metabolic dysfunction-associated steatotic liver disease, which is a fancy way to say MASLD, which we used to call non-alcoholic fatty liver. If you drink to excess, which is more than fourteen drinks per week in men and more than seven drinks per week in women, you then may be at risk for developing alcohol-associated liver disease. And because all these are combined, liver disease is actually very, very common.

Once your provider thinks you have liver disease, then the next step is to determine how it's damaged the liver over time. Because when the liver gets inflamed, it can cause scarring as it tries to heal itself, and that scarring is called fibrosis. Over time, this fibrosis, as I've mentioned, can progress to cirrhosis, which puts you at risk for developing liver failure and needing a liver transplant or developing hepatocellular carcinoma or liver cancer.

In the past, the best way we had to determine that was to perform a liver biopsy. And this is a routine outpatient procedure, but it does involve placing a small needle into the liver to get a piece of liver tissue that we can then look at under the microscope. And until 20 years ago, liver biopsy was the primary way that we assessed for liver scarring or fibrosis.

Host: I see. And. Doctor maybe now would be a time to talk about the function of the liver. I didn't pay enough attention in biology class back in the day. So, the liver's function is what?

Dr. Richard Sterling: So, the liver is the largest internal organ in the body and, of course, as a liver specialist, I think it's the most important organ in the body. The liver functions, in many ways, its use is as a filter. Everything that you take in through your mouth and into your gut gets absorbed and has to pass through the liver before it gets to the rest of the body. The liver is primarily involved with making many of the proteins that your body needs to use, and the liver is also involved in metabolism. So, anything that you take in, the liver may have to metabolize it or convert it to some other substance that your body can use.

Host: Okay, interesting. Doctor, how and why were you able to create the FIB-4 index?

Dr. Richard Sterling: During my fellowship training, which was almost 30 years ago, we were doing approximately twenty liver biopsies a week. And at that time, I was thinking, "Who had the bright idea to stick a large needle into a very vascular organ?"

And so far, I saw an opportunity to develop a non-invasive test to assess liver fibrosis. And as I've said, the only thing worse than doing a liver biopsy yourself is either teaching someone else how to do it or having one done on yourself. And at that time, again, this is now going back into the early 2000s, we only really had liver enzymes. And the main ones that we talk about is something called the aspartate aminotransferase, or the AST, and the alanine aminotransferase, or the ALT. And we knew that when one was higher than the other, it suggested that someone had developed advanced scarring of the liver. And we also knew that platelet counts, which is something that your bone marrow makes, often when your liver gets very scarred, the platelet count can drop, because of the spleen that drains into the liver gets kind of backed up or congested, and that can cause the platelet count to drop.

And at that time, we were using a scoring system for viral hepatitis, which was the most common liver disease that we were seeing. And therefore, at that time, what I really wanted to know was, did a patient have advanced stage scarring or stage III to IV, where stage IV is cirrhosis, from those with little or almost no scarring?

So, while I was completing my master's degree in biostatistics at that time as part of an NIH or National Institute of Health Career Development Award, I was fortunate to be participating as a clinical site at a very large international trial looking at treating hepatitis C. And from this dataset, I requested laboratories and the liver biopsy data, and also the statistical support from the company who was doing the trial.

And from that, we were able to develop this novel index to separate those who had advanced fibrosis from those with lesser degrees of fibrosis. And when we developed this analysis, initially, the factors were older age, and that was because people who had the disease longer were more likely to have more scarring. So, we thought age might be an important factor. We looked at AST, which is again one of those liver enzymes. And we also looked at a factor of clotting called the INR, which is again a routine test that we got, and platelet counts. However, several patients were missing some of these factors. And therefore, we ended up going, "Well, what's the next one in line that might have significance?" And we used the other liver enzyme, the ALT that I mentioned, in the selection process, and that was available on everybody. And it actually turned out to work quite as well.

And so, using these routine tests, including this AST to ALT ratio, which we knew was associated with more scarring in the liver, platelet count, the lower was more likely to be in patients with more scarring, and age as a surrogate for maybe how long you've had the disease, as well as my newfound knowledge of biostatistics, I was able to develop the Fibrosis 4, the FIB-4 index. And that was published now 20 years ago in 2006 in the prestigious journal, Hepatology.

Host: Interesting. And was it immediately accepted, Doctor?

Dr. Richard Sterling: Not really. It took a little bit of time because everybody with any new simple test didn't believe that such a simple test could work as well. Certainly, there have been many, many, many other types of non-invasive assessments to try to assess that. And many of them work fairly well, but very few of them are as simple as the FIB-4 index. And every time they're compared to the FIB-4 index, they may not work that much better. But it did take some time, particularly with the evolution of what I previously termed as MASLD, which we used to call fatty liver. Now that that's become so common, most of the societies and agencies were figuring out the best way to identify patients, and they kept turning back to the FIB-4, which turned out to work pretty well.

Host: And, doctor, let me ask, are there lifestyle changes that can influence the FIB-4 score over time for a patient?

Dr. Richard Sterling: Absolutely. And when you have any kind of liver damage, the goal is to try to reduce first the cause, which may be leading to the inflammation, and that can then hopefully either improve the scarring in the liver or keep it from getting worse, and that's how you really can improve your liver health.

Sometimes when we treat certain diseases, you can actually reverse the scarring in the liver if it hasn't gotten too bad. So, for example, if you have viral hepatitis, we can go ahead and we can treat that. We have excellent treatments for hepatitis C where we can cure almost everybody with a two to three-month course of just some pills. Or if you have viral hepatitis B, we can suppress it with medication and that can lead to liver improvement in your liver health. And if you have fatty liver disease, which is now again one of the most common, you can do things like control your diabetes, lose weight, and we also now have specific treatments that have been approved for fatty liver that can also reduce your liver damage.

Host: Wow, very good. And how frequently should a patient have the FIB-4 index done?

Dr. Richard Sterling: Well, I think it kind of depends on what the initial test is. So, if your FIB-4 score is low, and for those of you keeping a score at home, that would be anything less than 1.3, then that FIB-4 can be calculated whenever your routine labs are done. But it really should be done every couple of years just to see if things stay low.

And if that score stays persistently low over time, you're very unlikely to have any significant liver scarring. However, if the score increases or if your clinical course changes, you have a new disease or something's happening, then that may suggest either that the initial score was falsely low or that something is going on in your liver; and therefore, you need to be evaluated by a specialist.

Host: Like with so many things in health, early detection is always a key. With regard to liver disease and the FIB-4, I would guess early detection can help potentially long-term outcomes.

Dr. Richard Sterling: Absolutely. I think many people thought, back in the day, because we didn't have a lot of great treatments for either viral hepatitis and, until the last two years, we had no treatment for fatty liver, most people either didn't really want to know if they had liver disease or if they did, they said, "Well, what really can you do about it?" But now, as I mentioned, we've got great treatments for viral hepatitis. We have two new treatments for fatty liver disease. And of course, alcohol-associated liver disease is very common, and having an elevated FIB score might go ahead and incentivize people to stop drinking.

Host: Once someone's had a FIB-4, what happens next?

Dr. Richard Sterling: So, I think you should discuss the results with your doctor and ask, is there something other than liver disease that can be impacting the results? Because again, this is an index, and a low score is very good for telling you that you don't have a problem. But if the FIB-4 score is up a little bit, then I think you have to look at is it coming from liver disease or is it coming from something else? And so, that's again, where you might need to go ahead and see a specialist who can help you sort that out.

Host: What's the role of FIB-4 now, 20 years later? How are liver specialists using the results?

Dr. Richard Sterling: So, the FIB-4 right now is really used as the initial screening test. And as you've mentioned, it's recommended by all the GI and liver societies as well as many of the diabetes societies. If the FIB-4 is low, then it can be repeated at the next visit and every couple of years. If it's increased, then you're probably going to need some additional testing, and you might need a referral to either a gastroenterologist or a liver specialist, depending on what's available in your area.

As a liver specialist, the FIB-4 really offers me a quick and easy way to check for liver health. And it helps predict who might be at higher risk for developing complications such as I've mentioned, cirrhosis or liver cancer, and it helps me to identify those who I'm going to need to follow more closely.

Host: Doctor, you've shared a lot of great information. Is there anything else you'd like to add?

Dr. Richard Sterling: So, never in my wildest dreams did I imagine the impact that the FIB-4 index would have, not only on liver health or diseases that have really nothing to do with the liver. The FIB-4 has been used to predict the severity of COVID-19, but I think that never in my wildest dreams that I would imagine it would warrant a 20th year anniversary. And it's not clear if the FIB-4 would have lasted this long if I changed the name, for example, if I called it the Sterling Index, who knows if it would be used.

Some people ask me if I would have trademarked it. I didn't do that because I wanted it to be widely available to everybody, and I constantly get asked, if there's permission to use it, and I give it every time that I'm asked. And not a month goes by that the FIB-4 has not been used in some study that's published in one of our major journals. And when I developed it, I think, again, I was at the right place. It was during the right time in my career. I had access to the data that I needed, and I had very supportive mentors.

Host: Well, Doctor, congratulations on that. You've done a wonderful thing, and it's helped so many people and will continue to do that. And you certainly are to be congratulated.

Dr. Richard Sterling: Thank you, Carl.

Host: To make an appointment with a VCU Health hepatologist, call 833-828-5487. To learn more about the efforts of the Stravitz-Sanyal Institute to research and develop new treatments for liver patients, visit its website at liverinstitute.medschool.vcu.edu. If you enjoyed this podcast, please share it on your social channels and check out the full podcast library at vcuhealth.org/podcast for more topics of interest. I'm Carl Maronich. And this is Healthy with VCU Health. Thanks for listening.