The Clinical Course of Untreated Gaucher Disease in 22 Patients Over 10 Years: Hematological and Skeletal Manifestations.
Authors: Piran Siavash , Roberts Andrew , Patterson Mary Anne , Amato Dominick 
Published: April 2020

Abstract
Gaucher disease (GD) is a lysosomal storage disorder characterized by anemia and thrombocytopenia, hepatosplenomegaly, and skeletal involvement. The management of Gaucher disease was improved by the development of enzyme replacement therapy (ERT). However, the bone response to ERT is generally slower compared to other clinical manifestations. Some have recommended the early use of ERT to prevent the development of severe skeletal complications. Because we have access to over 30 untreated patients in Ontario, we questioned the extent to which the bony complications progress in severity over a long period of time. We examined retrospectively the natural history of GD and the extent of skeletal manifestations in 22 untreated type 1 GD adult patients (mean age 49 ± 3.3, range of 20–81 years). Ten patients were N370S homozygotes and twelve were compound heterozygotes. The patients were followed for a median of 9.5 years (range of 3 to 16 years). Assessments included complete blood counts (CBC); levels of angiotensin converting enzyme (ACE), ferritin, and chitotriosidase; liver and spleen volumes; and occurrences of bony complications. Dual Energy X-ray Absorptiometry (DEXA), Magnetic Resonance Imaging (MRI) of femurs, skeletal survey, and plain radiography were utilized to assess bony complications in 21 patients. Hemoglobin (Hb) concentration did not significantly change over time (mean baseline concentration of 12.8 ± 0.27 g/dL vs mean recent concentration of 12.6 ± 0.37 g/dL, p = 0.65). Mean platelet count also remained relatively stable over time (mean baseline count of 138 ± 13 × 109/L vs mean recent count of 138.5 ± 18 × 109/L, p = 0.98). Mean ferritin and ACE concentrations were elevated and were stable over time. Liver volumes decreased over time (mean baseline liver volume of 1.2 × normal (N) vs mean recent volume of 1.06 × N, p = 0.27) and 6/21 (29%) patients had moderate hepatomegaly (liver volume ≥ 1.25 × N). Spleen volumes remained stable over time (mean baseline spleen volume of 6.4 × N vs mean recent volume of 5.1 × N, p = 0.56). None of the changes was statistically significant. Three of 19 (15.8 %) patients had moderate splenomegaly (spleen volume ≥ 5 × N), 2/19 (10.5%) had severe splenomegaly (spleen volume ≥ 15 × N), and 2/22 (9%) had splenectomy. The most common skeletal manifestations were infiltration of the bone marrow in 15/21 (71%) patients followed by osteopenia in 14/21 patients (67%), and infarctions in 6/21 (29%) patients. Other bony complications included osteoporosis in 3/21 (14%), avascular necrosis (AVN) in the left knee and femur in 1/21 (5%), and osteolysis in 1/21 (5%) patients; there were no cases of fractures. Three of 21 (14%) patients developed new infarcts (2N370S homozygous patients) over time, 1/21 (5%) developed AVN, and 4/21 (19%) had an increase in the degree of osteopenia. There were no significant differences observed between the N370S homozygous and compound heterozygous patients. Although GD and its skeletal complications progress in severity in some patients, our results suggest that GD complications including bony disease may stabilize over time. Therefore, early use of ERT may not be necessary in all type 1 GD patients.