The clinical detection of hepatomegaly and splenomegaly—abnormal enlargement of the liver and spleen, respectively—requires a comprehensive evaluation, as numerous underlying conditions may be responsible, including metabolic, congestive, neoplastic, infectious, toxic, or inflammatory etiologies. Within metabolic disorders, lysosomal storage diseases (LSDs) are a rare and ultra-rare group, collectively affecting approximately 1 in 5000 live births. These disorders arise from genetic mutations impacting lysosomal enzymes, membrane proteins, or transporters, causing intracellular accumulation of metabolites and subsequent organ dysfunction. Advances in early diagnosis and targeted therapies have improved survival and quality of life for many affected individuals. Consequently, LSDs should be considered in patients presenting with hepatosplenomegaly across all age groups. This review outlines the diagnostic evaluation of hepatosplenomegaly with particular focus on LSDs, highlighting clues from patient history, physical examination, laboratory findings, and imaging. Molecular testing, preferably over biopsy, is emphasized, with enzymatic analysis recommended when possible.
