Using Noninvasive Testing to Guide MASH Treatment Decisions, With Naim Alkhouri, MD

The rapid emergence of pharmacologic options for metabolic dysfunction-associated steatohepatitis (MASH) has introduced a new set of clinical challenges, particularly around identifying which patients are appropriate candidates for treatment.

With both resmetirom and semaglutide now approved by the US Food and Drug Administration for patients with F2-F3 fibrosis, professional societies have emphasized the need for careful noninvasive assessment to avoid treating individuals with cirrhosis until more data become available. However, the practical application of these recommendations is not always straightforward, as liver stiffness thresholds commonly used to exclude patients may inadvertently prevent some individuals with advanced fibrosis from receiving therapies that have the potential to reverse disease progression.

“We know from clinical practice that many patients with liver stiffness above 20, between 20 to 25, may actually have stage 3 fibrosis, not cirrhosis, and if you exclude them automatically, they will miss the opportunity to be treated with the treatment that can reverse fibrosis,” Naim Alkhouri, MD, chief academic officer of Summit Clinical Research and director of the Steatotic Liver Program at North Shore Gastroenterology, explained to HCPLive.

At the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025, Alkhouri presented research examining the performance of noninvasive tests (NITs) in identifying F2/F3 or F4 fibrosis in patients with LSM 15-25 kPa in a large multicenter database of patients with biopsy-proven MASH.

Patients with LSM 15-20 kPa or LSM 20-25 kPa were identified for further analysis. Comparisons were made between those found to have F2/F3 on biopsy versus F4, and NIT performance was compared to biopsy results.

Of 18,402 patients reviewed, 4326 had baseline liver biopsy and LSM results, 882 of whom had LSM between 15-25. Among patients with LSM between 15-20 kPa (n = 586, 66%; n = 354 F2/F3 and n = 232 F4) and 20-25 kPa (n = 296, 34%; n = 141 F2/F3 and n = 155 F4), patients with F4 fibrosis were significantly older (P <.001), more likely to be White (P <.001), and had lower BMI (P <.001).

In patients with LSM 15-20 kPa, investigators noted model performance was highest using Agile 4 (AUC, 0.76; 95% CI, 0.69-0.83), followed by platelet count (AUC, 0.71; 95% CI, 0.66-0.76) and FIB-4 (AUC, 0.69; 95% CI, 0.64-0.75). Among the LSM 20-25 kPa group, platelet count had superior performance (AUC, 0.75; 95% CI, 0.69-0.82), followed by FIB-4 (AUC, 0.73; 95% CI, 0.66-0.80), and Agile 4 (AUC, 0.70; 95% CI, 0.60-0.79).

Combining all tests resulted in an AUC of 0.76 (95% CI, 0.69-0.82) in the 15-20 kPa group and 0.75 (95% CI, 0.66-0.84) in the 20-25 kPa group. To reach ≥90% sensitivity, for the Agile 4 score, a cutoff value of 0.104 was needed in the 15-20 kPa group and 0.099 in the 20-25 kPa group.

“We hope that these recommendations will be useful to providers when they have elevated liver stiffness and they're not sure if they need to proceed with treatment with resmetirom or semaglutide or say no because this patient has cirrhosis,” Alkhouri said.

Editors’ note: Alkhouri reports relevant disclosures with Altimmune, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Rivus, Takeda, and others.

References

1. Alkhouri N, Schattenberg J, Patil R, et al. Utility of FIB-4, Agile 4, and Platelet Count to Rule Out Cirrhosis on Biopsy in Patients with LSM Between 15-25 kPa: A Multi-Center Cohort Study. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

2. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed November 20, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

3. Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed November 20, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash