Genetic and biochemical screening for Gaucher disease and lysosomal acid lipase deficiency in patients with hepatosplenomegaly of unknown etiology

Background: Gaucher disease and lysosomal acid lipase deficiency (LALD) are rare lysosomal lipid storage diseases caused by mutations of the GBA and LIPA genes, respectively. These mutations cause deficiency of the lysosomal enzymes β-glucocerebrosidase and acid lipase. Both diseases result in hepato- and/or splenomegaly and an increase of the serum surrogate marker chitotriosidase, which represents a macrophage activation marker.

Patients and methods: In this study we screened patients with hepatosplenomegaly of unknown origin at a tertiary academic referral center. We determined the enzymatic activities of chitotriosidase, β-glucocerebrosidase and acid lipase with biochemical arrays. Common LIPA and GBA gene variants were genotyped with Taqman assays and direct sequencing.

Results: Between 2010 and 2014 we identified 201 patients with hepato- and/or splenomegaly of unknown etiology origin at our center (median age 55yrs [21 – 83]; 69 women [34%]). Among them, 136 patients (67.7%) presented with spleen size > 110 mm; hepatomegaly was diagnosed in 100 patients (49.8%), and combined hepatosplenomegaly was present in 35 patients (17.4%). Overall, we identified 36 patients (27.4%) with serum chitotriosidase activities ≥250 nmol/ml/h. β-glucocerebrosidase and acid lipase activities were within normal ranges in all patients tested. In this cohort, we could identify a single heterozygous carrier of the mutation p.N370S in the GBA gene only; the mutation p.L444P was not detected. The E8SJ mutation in the LIPA gene was not observed in our patients either. Chitotriosidase activities declined significantly with age (-2,66 nmol/ml/h, p < 0,003), and lysosomal acid lipase showed a seminar trend.

Discussion: Apparently hepatologists do not miss a large number of patients with lipid storage disease. For the identification of unknown patients with Gaucher disease or LALD, screening efforts should not only include liver centers but other units specialized in pediatric care, lipid disorders and orthopedics. In addition, newborn screening for Gaucher disease and LALD might be considered.