Diagnostic Performance of NITs Across MASLD Subgroups, With Zobair Younossi, MD, MPH

As metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise globally, the need for accurate, accessible risk stratification has never been greater. Historically, clinicians have relied on liver biopsy to identify the subgroup of patients with metabolic dysfunction–associated steatohepatitis (MASH) at the greatest risk for progression to cirrhosis, liver cancer, and liver-related mortality.

Because biopsy is invasive, costly, and not without risk, the field of hepatology has grown increasingly reluctant to rely on it for widespread screening and longitudinal monitoring. As Zobair Younossi, MD, professor and chairman of the Global NASH Council, explains in an interview with HCPLive, the past decade has been defined by efforts to develop noninvasive alternatives that can match biopsy not only in staging accuracy but also in predicting long-term outcomes.

“NITs were first established on a liver biopsy to see if they're accurately predicting the stage that we want to look for,” he explained. “More recently, there is also data to suggest that these NITs predict outcome as well as liver biopsy, and maybe sometimes even better than a liver biopsy, which makes them ideal for clinical use and also for use in clinical trials.”

Specifically, Younossi references 3 main categories of noninvasive tests:

• Clinical algorithms like FIB-4
• Blood-based tests like ELF and PRO C3
• Imaging modalities like VCTE, shear wave elastography, and MRE

He additionally describes combination tests leveraging combined clinical data from existing NITs, including the FAST score, AGILE 3, and AGILE 4.

Younossi’s research, a trio of sequentially published papers, has explored how NITs perform across regions, how well they predict liver-related outcomes compared with biopsy, and how their accuracy varies in key subgroups.

Of note, while all NITs demonstrated outcome prediction comparable to, and in some cases better than, biopsy, their performance was not uniform. He says FIB-4, for example, performs less reliably in patients at extremes of age and in those with diabetes, and regional variability was observed, with weaker performance in South Asia and Latin America. In contrast, liver stiffness measurement was less affected by age or diabetes but was influenced by severe obesity. Among the available tools, AGILE 3 and AGILE 4 emerged as particularly stable across regions and subgroups.

Clinically, Younossi emphasizes a stepwise algorithm. FIB-4 remains the recommended first-line test to identify patients at low risk who can be monitored periodically versus those who warrant second-line assessment with VCTE or ELF. Beyond risk stratification, he says NITs now guide treatment selection, particularly for noncirrhotic MASH patients eligible for recently approved agents such as resmetirom or semaglutide and enable longitudinal monitoring.

Editors’ Note: Younossi reports relevant disclosures with Intercept, Cymabay, Boehringer Ingelheim, Ipsen, BMS, GSK, Novo Nordisk, Siemens, Madridgal, Merck, Aligos, Akero, Sanofi and Abbott.

References

1. Younossi ZM, de Avila L, Petta S, et al. Diagnostic Accuracy of Non-Invasive Tests for MASLD Across Age, Type 2 Diabetes, and Obesity Subgroups: A Multinational Study. Clin Gastroenterol Hepatol. Published online January 28, 2026. doi:10.1016/j.cgh.2026.01.016

2. Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed February 12, 2026. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash

3. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed February 12, 2026. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash