Abstract

Gaucher disease (GD) and acid sphingomyelinase deficiency (ASMD) are rare lysosomal storage disorders with chronic visceral forms that often present in adulthood with nonspecific hepatic or hematologic signs. Hepatologists are frequently among the first specialists to encounter these patients, particularly when evaluating unexplained hepatosplenomegaly, thrombocytopenia, dyslipidemia, or liver test abnormalities. However, due to clinical overlap with common liver conditions, such as metabolic dysfunction-associated steatotic liver disease and cryptogenic cirrhosis, both GD and ASMD remain significantly underdiagnosed or misdiagnosed. Lack of disease awareness, diagnostic inertia, and the absence of structured pathways contribute to substantial delays in treatment initiation. This review aims to equip hepatologists with practical tools to improve early recognition of GD and ASMD through the application of red flag-based diagnostic flowcharts. Drawing on current literature and field experience, we present an integrated hepatology-focused approach that begins with common clinical triggers and guides enzyme testing and referral decisions. We further describe the development and implementation of the Italian “GD & ASMD – Closer to Care” initiative, which combined field-based training, diagnostic network-building, and pilot screening activities across referral hepatology centers. Finally, we explore emerging perspectives, including the role of newborn and at-risk populations screening and exome sequencing in cryptogenic and multisystemic liver diseases. While advanced diagnostic tools promise future improvements in early detection, actionable awareness, and risk-based screening remain the cornerstone of the current diagnostic strategy. By adopting standardized flowcharts and promoting interdisciplinary collaboration, hepatologists can play a pivotal role in closing the diagnostic gap for GD and ASMD, ensuring earlier diagnosis and access to disease-specific therapies for affected individuals.