Low lysosomal acid lipase activity is associated with histological progression of metabolic dysfunction-associated steatotic liver disease

Background and purpose of the study: Liver inflammation and fibrosis are the key determinants of long-term adverse outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, identifying progressive forms of MASLD is crucial. Lysosomal acid lipase (LAL), a central enzyme in intracellular lipid hydrolysis, has been reported to be reduced in MASLD and linked to liver injury. Aim: To evaluate whether baseline LAL activity predicts long-term progression of MASLD. Methods: We prospectively followed up 144 adults with biopsy-proven MASLD for a minimum of 5 years (median 8.1). All patients underwent a FibroScan® at baseline and follow-up and 94 of them also had paired liver biopsies. LAL activity (expressed as LAL/platelet-LAL/ptls) was measured on dried blood spots. Liver disease progression was defined by meeting of the histological endpoint at follow-up (i.e., development of MASH and/or NAS worsening ≥ 1 point and/or fibrosis progression ≥ 1 stage) or by liver stiffness measurement (LSM) worsening at Fibroscan. Results: Among the 94 biopsied patients, 26% met the composite histological endpoint and had significantly lower baseline LAL/ptls ratio, higher HOMA-IR, CAP and LSM. In particular, lower LAL/ptls was strongly related to the worsening of inflammation. In multivariate analysis, lower ln-transformed LAL/ptls ratio independently predicted histological progression (OR 0.51, 95% CI 0.04-0.60, p = 0.018). No association emerged between baseline LAL/ptls ratio and non-invasive progression by FibroScan. Conclusions: Lower LAL/ptls ratio identifies MASLD patients at increased risk of histological progression and complements non-invasive tools by reflecting biological pathways linked to inflammation.