MASH Follow-Up Gaps Start With Low Recognition: Rohit Loomba, MD

Lack of recognition that fatty liver disease can silently progress to cirrhosis and that fibrosis from metabolic dysfunction–associated steatohepatitis (MASH) can be treated is the most important gap behind missed follow-up testing among at-risk patients in primary care and endocrinology, said Rohit Loomba, MD, MHSc, director of the MASLD Research Center and chief of the Division of Gastroenterology and Hepatology at the University of California, San Diego.

In an interview with The American Journal of Managed Care^® (AJMC^®), Loomba discussed why patients flagged as intermediate or high risk by the Fibrosis-4 index (FIB-4) often do not get follow-up testing, how differing laboratory cutoffs for alanine aminotransferase (ALT) can cause abnormal results to be overlooked, what outcomes data show about magnetic resonance (MR) elastography, and what it could take for regulators to accept noninvasive tests in place of liver biopsy in drug trials.

This interview has been edited for clarity.

AJMC: Your research has found that among primary care patients flagged as intermediate or high risk by FIB-4, few get that follow-up test, like elastography. What does that gap tell you about where the diagnosis pathway breaks down?

Loomba: I think the most important thing is lack of recognition, particularly in the primary care setting and also among endocrinologists, that fatty liver [metabolic dysfunction-associated steatotic liver disease (MASLD)], which affects one-third of US adults,¹ can progress to cirrhosis. Then for patients who have significant liver disease related to fat deposition in the liver, which we identify as MASH-related fibrosis, there's a treatment that can reverse it, and we can prevent that progression. I think there is a lack of awareness about the disease and its silent progression without any symptoms and that there is a way that we can identify it noninvasively and reverse it. I think all those gaps are there.

AJMC: For diseases like diabetes and chronic kidney disease, screening has built-in follow-up loops. When there's an abnormal hemoglobin A_1C, that result reliably leads to next steps for the patient. Why do you think MASH screening hasn't achieved that same reliability, and what would it take to get there?

Loomba: MASH is a liver disease, so typically somebody would need to see a liver doctor to make that recognition, but the majority of patients who have suspected MASH are sitting in primary care or with endocrinologists, and they're not aware that this disease can lead to significant problems in a subset of patients. Also, if you look at it from a primary care viewpoint, 60% to 70% of patients may have disease that is not advanced. And about 10% to 15%—depending on the presence of type 2 diabetes—may have significant advanced fibrosis, stage 3 or stage 4.² Identifying that subgroup would require somebody to maybe screen 8 patients to have 2 patients who need to be treated. That would also require additional time and knowledge to look for those patients, and then tests may not be readily available for screening among primary care physicians. I think that's something that is a problem.

We came up with clinical prediction rules such as FIB-4, which includes age, ALT [alanine aminotransferase], AST [aspartate aminotransferase], and platelets. Age, ALT, and AST come from a complete metabolic profile, and then a complete blood count provides your platelets. Those may be available among patients sitting in primary care, and somehow if you can automatically calculate that FIB-4, then you can risk stratify just based upon blood tests somebody who has low risk, intermediate risk, or advanced risk. And then they can consider a referral or second-line testing with other fibrosis biomarkers.

AJMC: Most at-risk patients with an abnormal FIB-4 score can have normal liver enzymes. What can you tell me about that combination, and why does that get overlooked in primary care?

Loomba: The upper limit of ALT and AST could vary depending on the lab, and some labs have an upper limit of normal at 45 U/L, some have 50 U/L. But ALT of 30 U/L or higher is abnormal, and we've standardized that. We say that if anybody has an ALT of 30 or higher, that's abnormal for a man, and for women, it's 19 or higher.³ If I get my ALT tested here [California] and it's 35 U/L, and I get my ALT tested in North Carolina and it's 35 U/L, then the variability stays within 10% of that absolute number. If the lab has an upper limit of 50 U/L, that's the wrong upper limit.

What happens is a lot of primary care physicians are only seeing things in the report as green or black or red. If the number is not flagged as red, they're not paying attention to it. The issue is that for ALT, each regional lab or local lab may have a different cut point, and that's a problem. The upper limit of normal for liver specialists is 30 U/L or higher, and so anybody above that, which still could be within normal limits for your lab, is something you need to take care of and follow up on.

AJMC: Your research with the GOLDMINE study used magnetic resonance (MR) elastography as an imaging biomarker tied to hard MASLD clinical outcomes.⁴ How has validating imaging against actual clinical events, rather than just histology, changed how we view the predictive power of noninvasive tools for everyday practice?

Loomba: It's really important that the tools we use in clinical practice have prognostic significance. We have that data on MR elastography now, and we also have data for other liver stiffness measurements. Now, MR elastography, based upon our studies, is probably the most accurate noninvasive biomarker for detection of fibrosis, significant fibrosis, and advanced fibrosis. When identifying who needs to be treated, we could really separate out patients who have significant disease that requires treatment.

For clinical practice, when MRE [MR elastography] is not available, if people have FibroScan or liver stiffness assessment on vibration-controlled transient elastography, or VCTE, that can also be utilized to identify who needs to be treated. Studies by us and others have shown that although MR elastography is better than liver stiffness on FibroScan, FibroScan is also prognostic. Liver stiffness measurement in general, whether it's FibroScan or MR elastography, has prognostic significance. When the liver stiffness on MR elastography reaches 5 kPa, we think you have a pretty high likelihood of not having cirrhosis.⁵ If liver stiffness on FibroScan reaches 20 kPa or higher, we think somebody may have developed cirrhosis, particularly in the setting of low platelets. These tests are very useful; they have direct clinical implications, and they also have prognostic significance for hepatic decompensation and the need for liver transplantation.⁶

AJMC: Liver biopsy is rarely used in community practice, but it remains the regulatory standard for drug approval. Based on the data from studies like GOLDMINE, what do you think it would take for regulators to accept noninvasive imaging in place of biopsy for clinical trials?

Loomba: Last year, the FDA came up with a request for applications for noninvasive tests and biomarkers and put together guidance as to what those tests should be able to show. That way they can change regulatory guidance to have noninvasive biomarkers instead of liver biopsy as a test for regulatory approval, particularly for Subpart H approval [FDA Accelerated Approval pathway], similar to liver histology end points.^7,8 Currently, we are working as a field together, along with regulators, various sponsors, and the drug companies that are developing drugs, but also with Echosens, which is the maker of FibroScan, and also Resoundant, which is the maker of MR elastography, developing evidence and data that liver stiffness is not only associated with fibrosis today in the patient but also is prognostic for progression to cirrhosis and also for hepatic decompensation.

I'm attending the Precision Liver Symposium on November 4 in Denver right before AASLD [American Association for the Study of Liver Diseases], and the whole idea of that meeting is to look at noninvasive tests for cirrhosis and address reasonably likely surrogate end points for drug approval in MASH trials. The idea is that we could potentially use liver stiffness measurement by MR elastography or liver stiffness measurement on VCTE as reasonably likely surrogate end points, and there are 3 criteria that we want to show that both of these tests could meet. One is that the increase in liver stiffness is associated with clinical end points, such as progression to cirrhosis or hepatic decompensation. We have retrospective data that is available today, but we are also developing prospective data from some of our studies, such as GOLDMINE. Then we want to show that a significant increase in liver stiffness—such as a 20% increase in MR elastography or a 30% increase or a 5 kPa absolute increase on FibroScan—may be clinically meaningful. We want to show that the increase is associated with the worsening or progression of disease. The third idea is that an improvement in that is associated with improved survival.

We have to show all 3 of these in a package, and if the regulators buy it, then I think we can move the needle. Then the sponsors or pharma companies may actually have to show that their drug is doing that in an early trial, like a phase 2b, and present that data in support of a phase 3 for elimination of the need for a liver biopsy assessment. I think we are pushing the field forward, and that will happen based upon our discussions in the Precision Liver Symposium and other meetings that are tackling that.

References

1. Clark JM, Cryer DRH, Morton M, Shubrook JH. Nonalcoholic fatty liver disease from a primary care perspective. Diabetes Obes Metab. 2023;25(6):1421-1433. doi:10.1111/dom.15016
2. Noureddin M. Overview of metabolic dysfunction-associated steatohepatitis cirrhosis. Gastroenterol Hepatol (N Y). 2025;21(10):635-637.
3. Park JH, Choi J, Jun DW, Han SW, Yeo YH, Nguyen MH. Low alanine aminotransferase cut-off for predicting liver outcomes; a nationwide population-based longitudinal cohort study. J Clin Med. 2019;8(9):1445. doi:10.3390/jcm8091445
4. Sharpton S, Díaz LA, Pepin K, et al; GOLDMINE consortium. Global Longitudinal Assessment of MASLD Using Magnetic Resonance Elastography (GOLDMINE): a multi-center, international prospective cohort study of imaging biomarkers in MASLD clinical outcomes. Aliment Pharmacol Ther. 2026;64(3):334-344. doi:10.1111/apt.70696
5. Vasilevskyi V. What your FibroScan number says about your liver. AllClinicalTrials.com. September 14, 2026. Accessed October 29, 2026. https://www.allclinicaltrials.com/blog/fibroscan-results-explained
6. Ajmera V, Nguyen K, Tamaki N, Sharpton S, Bettencourt R, Loomba R. Prognostic utility of magnetic resonance elastography and MEFIB index in predicting liver-related outcomes and mortality in individuals at risk of and with nonalcoholic fatty liver disease. Ther Adv Gastroenterol. 2022:15:17562848221093869. doi:10.1177/17562848221093869
7. Anania FA, Hager R, Higgins K, Makar GA, Siegel J, Tran TT. Non-invasive tests: establishing efficacy for metabolic dysfunction-associated steatohepatitis beyond the biopsy—current perspectives from the Division of Hepatology and Nutrition, US Food and Drug Administration. Hepatology. 2026;84(1):321-327. doi:10.1097/HEP.0000000000001509
8. FDA accepts proposal for reasonably likely surrogate endpoint for ‘MASH’ all-cause mortality or liver-related events. US Food and Drug Administration. August 27, 2025. Accessed October 26, 2026. https://www.fda.gov/drugs/drug-alerts-and-statements/fda-accepts-proposal-reasonably-likely-surrogate-endpoint-mash-all-cause-mortality-or-liver-related