Stefano Romeo

The rising prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) poses a significant global health challenge, affecting over 30% of adults worldwide. MASLD is linked to increased mortality rates and substantial healthcare costs, primarily driven by its progression to metabolic dysfunction‐associated steatohepatitis (MASH), which can lead to severe liver complications including cirrhosis and hepatocellular carcinoma. Despite its growing burden, effective pharmacotherapy for MASLD/MASH has been lacking until the recent conditional approval of resmetirom by the FDA. Resmetirom, a liver‐targeted thyroid hormone receptor‐β selective drug, has shown promise in clinical trials for treating non‐cirrhotic MASH with moderate to advanced fibrosis. It has demonstrated efficacy in reducing hepatic fat content, improving liver histology (both MASH resolution and fibrosis improvement), and ameliorating biomarkers of liver damage without significant effects on body weight or glucose metabolism. Notably, resmetirom also exhibits favourable effects on circulating lipids, potentially reducing cardiovascular risk in MASLD/MASH patients. The safety profile of resmetirom appears acceptable, with gastrointestinal adverse events being the most common, though generally mild or moderate. However, long‐term surveillance is warranted to monitor for potential risks related to thyroid, gonadal, or bone diseases. Clinical implementation of resmetirom faces challenges in patient selection and monitoring treatment response, and will heavily rely on non‐invasive tests for liver fibrosis assessment. Nonetheless, resmetirom represents a landmark breakthrough in MASLD/MASH treatment, paving the way for future therapeutic strategies aiming to mitigate the multifaceted risks associated with this complex metabolic liver disease.

Summary Background and Aims The European Association for the Study of the Liver introduced a clinical pathway (EASL CP) for screening significant/advanced fibrosis in people at risk of steatotic liver disease (SLD). We assessed the performance of the first‐step FIB4 EASL CP in the general population across different SLD risk groups (MASLD, Met‐ALD and ALD) and various age classes. Methods We analysed a total of 3372 individuals at risk of SLD from the 2017–2018 National Health and Nutrition Examination Survey (NHANES17‐18), projected to 152.3 million U.S. adults, 300,329 from the UK Biobank (UKBB) and 57,644 from the Biobank Japan (BBJ). We assessed liver stiffness measurement (LSM) ≥8 kPa and liver‐related events occurring within 3 and 10 years (3/10 year‐LREs) as outcomes. We defined MASLD, MetALD, and ALD according to recent international recommendations. Results FIB4 sensitivity for LSM ≥ 8 kPa was low (27.7%), but it ranged approximately 80%‐90% for 3‐year LREs. Using FIB4, 22%–57% of subjects across the three cohorts were identified as candidates for vibration‐controlled transient elastography (VCTE), which was mostly avoidable (positive predictive value of FIB4 ≥ 1.3 for LSM ≥ 8 kPa ranging 9.5%–13% across different SLD categories). Sensitivity for LSM ≥ 8 kPa and LREs increased with increasing alcohol intake (ALD>MetALD>MASLD) and age classes. For individuals aged ≥65 years, using the recommended age‐adjusted FIB4 cut‐off (≥2) substantially reduced sensitivity for LSM ≥ 8 kPa and LREs. Conclusions The first‐step FIB4 EASL CP is poorly accurate and feasible for individuals at risk of SLD in the general population. It is crucial to enhance the screening strategy with a first‐step approach able to reduce unnecessary VCTEs and optimise their yield.