Fibrosis and Steatosis in MASLD/MASH

Our expert panel continues this series on MASLD and MASH, discussing how best to diagnose and quantify fibrosis through FIB-4, VCTE, MRE and other blood and imaging tests.

Robert Fontana, MD, is a professor of medicine and director of the Transplant Hepatology Fellowship Program at University of Michigan Medicine in Ann Arbor, Michigan. Manal Abdelmalek, MD, FAASLD, is a professor of medicine and director of the Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) Clinical Research Program at Mayo Clinic in Rochester, Minnesota. Juan Pablo Arab, MD, is associate professor of medicine and the inaugural director of Alcohol Sciences at the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University (VCU) Health in Richmond, Virginia.

Noninvasive Fibrosis Risk Assessment in MASLD and MetALD

• Fibrosis predicts clinically meaningful liver outcomes; steatosis may signal cardiovascular and metabolic risk. Fibrosis risk guides care pathways.
• FIB-4 supports primary care triage: <1.3 suggests low advanced fibrosis risk in appropriate contexts. Performance is limited below age 35 and above 65; a cutoff of 2 may improve performance above 65.
• Transient elastography guides specialist assessment: <8 kPa suggests low risk; 8–10 warrants further evaluation; >10, particularly >12, raises advanced fibrosis concern. Magnetic resonance elastography may clarify unreliable measurements. ELF is second-line, with cost and availability limitations.

Dr Fontana:

So let's talk a little bit about how significant is the liver. So first off, Manal, what matters? Is it fibrosis or steatosis? And how do you track those in clinical practice without doing a biopsy?

Dr Abdelmalek:

Well, when you talk to a hepatologist, what we care about I think is fibrosis because it's the one and only histologic feature even known to predict clinically meaningful outcomes as it relates to liver disease. That's not to say that steatosis isn't important because it potentially is a marker of increased cardiovascular risk, new onset diabetes, potentially worsening metabolic syndrome. But from a liver related outcomes, what matters to me is fibrosis. And I strive to assess whether my patients are certainly in a no risk category, no increased risk for advanced hepatic liver disease, or are at intermediate risk where they may potentially be eligible for pharmacotherapies, which we'll talk about later, or advanced hepatic fibrosis, in which case that really does change the care pathway I use. Patients with cirrhosis or advanced hepatic fibrosis need screening for hepatocellular carcinoma or if they fall into the Baveno criteria, screening for esophageal varices.

So I try and stratify based on fibrosis risk.

Dr Fontana:

So we talk about noninvasive tests, NITs, and really they kind of fall broadly into blood-based biomarkers and then imaging-based biomarkers. So Manal, what are the blood-based biomarkers that any doc listening to this could use in their practice? Heard about FIB-4, heard about ELF scores. Tell us a little bit about those and how you use them for this risk stratification of fibrosis severity.

Dr Abdelmalek:

Yeah, so I encourage nonhepatology practices, community-based doctors, primary care, endocrinology--the FIB-4 score really is an excellent prognosticative tool for its negative predictive value and discerning those patients who are not at risk for advanced hepatic fibrosis in those practices. Now, there are some caveats. You have to use it with understanding that it does not perform well in patients who are under the age of 35 or older than the age of 65. However, if that FIB-4 score is under 1.3 and used in the right clinical context, those patients are not the type of patients who need to see me or us as specialists. I do not use a FIB-4 regularly in my clinical practice as a hepatologist because of the enrichment. By the time patients come to see me in a liver practice, they have multiple metabolic risk factors, they have elevated liver aminotransferases, and I go straight to point-of-care assessment of risk stratification with imaging-based biomarkers, predominantly transient elastography, but may use magnetic resonance elastography as a risk stratifier.

If I have concerns, maybe I'll check a FIB-4, but really in my hands I'm using an image-based biomarker to further risk stratify beyond the FIB-4.

Dr Fontana:

So it sounds like you like to use the FIB-4 as a triaging tool, if you will, maybe even before the referral comes to you, or maybe you rescreen the referral and you can calculate the FIB-4 if it isn't done, and then you use imaging as a secondary. JP, what's your approach there in Virginia?

Dr Arab:

Yeah, it's same. I think FIB-4 is first and always for everyone. So as a screening tool with the caveats that Manal was mentioning, you can increase, for example, in population more than 65 years old, they cut off to 2, for example, to improve the performance in that population. But yeah, I will say FIB-4 first always for everyone. We actually have it incorporated in our EMR, so it's very easy. Doctors don't need to calculate it. It's there and there is an alert that will tell them FIB-4 is elevated, consider referring to hepatology. There are other blood-based biomarkers such as ELF. For me, ELF is second-line, is a commercial test, so there is cost associated and also it's not always available. But yes, FIB-4 is the first line.

Dr Fontana:

So that ELF panel, it's 3 fibrotic matrix turnover markers, right? I believe it's ProPep, hyaluronic acid, and TIMP-1. And I agree that even in a major medical center, it's oftentimes a send out. It takes 5 days to get a result back and it's costly. So I think the FIB-4 you can calculate off a CBC comp and widely, widely available. So probably has more practical utility, although interestingly, a lot of clinical trials use ELF tests, which we'll talk about. So it sounds like we have a screening paradigm, we have the imaging that prompted all this. So now you have this idea of point of care, transient elastography, and then maybe a MR. So JP, when do you do transient elastography with suspected MASLD or MetALD, and when do you do MRE?

Dr Arab:

So my practice is similar to Manal’s. So the patients come to me refer because there is a high suspicion, either an elevated FIB-4 or is not what we will call isolated steatosis or simple steatosis. So I will do VCTE on all those patients because they already are in the high suspicious group. Either they are more than 50 years old, multiple cardiometabolic comorbidities, or very frequently in my clinic heavy alcohol consumption. So I will use BCTE or transient elastography for most decision. And roughly I will say if the patient VCT is below 8 kilopascals, we are in the safe zone. If there is between 8 and 10, well, we need to do more workup. And if there's more than 10, especially more than 12, I concern about advanced fibrosis, more than 15, I think about cirrhosis and more than 20 or 25 as Bovino suggested, you need to think about portal hypertension. That's kind of the rule of thumb, how you use it.

When to use MRE is, again, I have the VCTE as a point of care in my clinic. VCTE is in radiology department, so it needs to be a schedule and then you get the result ideally weeks, but it can be even months down the road. So I will use it for patients where I cannot be sure that the VCTE is reliable. I have a very high interquantity ratio, which is kind of the way how we measure how close the different measurements were between the 10 of them. If they are very spread out, you are not sure if you are being accurate. And that can happen in patients, for example, with obesity or very high BMI or central adiposity. Can happen also in patients with ascites, but usually if you have ascites, you have very clear imaging of cirrhosis.

But it could be the scenario where you have a patient that it has ascites and you are not entirely sure if this is coming from the liver or not. So that is mostly the scenario where I use magnetic resonance elastography.