Acid sphingomyelinase deficiency and Gaucher disease: Underdiagnosed and often treatable causes of hepatomegaly, splenomegaly, and low HDL cholesterol in lean individuals

Background: Acid sphingomyelinase deficiency (ASMD) and Gaucher disease type 1 (GD1) are rare inherited sphingolipid disorders with multisystemic manifestations, including liver disease and dyslipidemia. Despite effective treatments, insufficient disease awareness frequently results in diagnostic delays during which irreversible complications occur. We delineated the shared and distinctive features of hepatic, splenic, and lipoprotein phenotypes in ASMD and GD1.

Methods: We analyzed baseline hepatic, splenic, and lipoprotein phenotypes of untreated adults in pivotal trials of ASMD (ASCEND, N=36) and GD1 (ENGAGE, N=40).

Results: The mean cohort ages were 34.8 years in ASMD and 31.8 years in GD1. Most patients had normal or low body mass index. Moderate hepatosplenomegaly (mean volume in multiples of normal) was common in both cohorts (hepatomegaly 1.53±0.42 and 1.40±0.32, respectively; splenomegaly 11.45±4.36 and 13.20±5.91, respectively). Liver function tests were mildly elevated in ASMD but normal in GD1. In both disorders, mean HDL cholesterol (mg/dL) was profoundly low (22.23±9.14 ASMD; 26.25±8.08 GD1) and correlated inversely with liver volume (r=-0.45 ASMD, p=0.005; r=-0.50 GD1, p=0.001) and spleen volume (r=-0.60 ASMD, p=0.0001; r=-0.63 GD1, p<0.0001). Mean LDL cholesterol (mg/dL) was elevated in ASMD (145.86±49.80) but low in GD1 (68.85±22.53). HDL cholesterol correlated inversely with serum concentrations of lyso-sphingomyelin in ASMD (r=-0.48, p=0.003) and glucosylsphingosine in GD1 (r=-0.63, p<0.0001).

Conclusions: ASMD and GD1 should be considered in differential diagnosis of patients with unexplained liver and lipid abnormalities, especially young, lean adults with very low HDL and hepatosplenomegaly. HDL emerged as a potential biomarker of disease activity in these sphingolipid disorders.