الفهرس 
Gaucher DiseaseOnly 14 pages are availabe for public view
 |  | from | 234 |  |  |
| | | from | 234 | | |
Abstract
G
aucher disease (GD), a common lysosomal storage disease, is caused by mutations in GBA1 with resultant defective glucocerebrosidase function and the consequent accumulation of its substrate glucosylceramide in macrophages and other cell types. Onset in childhood is usually predictive of a severe, rapidly progressive phenotype and children with type 1 GD are at high risk for morbid complications. Complications include chronic liver disease and hepatopulmonary syndrome which has unfavorable outcome. Long term liver complications that have been associated with GD include fibrosis and cirrhosis.
Screening for liver fibrosis could be of additional value in the management of GD patients. FibroScan, or transient elastography (TE), non-invasively assesses liver fibrosis and presents comparable performance to liver biopsy to predict liver-related outcomes in patients with chronic liver diseases.
Progranulin (PGRN) is recognized for its role in a variety of physiologic and disease processes, including immunomodulation, cell growth, wound healing, host defense and inflammation. PGRN has been shown to play an important role in lysosomes, and homozygous mutation of the GRN gene results in neuronal ceroid lipofuscinosis. It has been reported as a novel disease modifier in GD. The role of PGRN in liver disease and fibrosis has been shown in some studies; however, to our knowledge, the relation between PGRN and liver fibrosis among patients with GD has not been previously explored.
The aim of the study was to determine PGRN levels in pediatric patients with GD and assess its role as a potential marker for disease severity and relation to liver stiffness by TE.
This study included 51 GD patients (29 males and 22 females) recruited from the regular attendants of the Pediatric Hematology Clinic, Pediatric Hospital, Ain Shams University. The median age of GD patients was 9.5 (IQR, 4 – 14) years. Twenty-one patients had type 1 and 31 had type 3. Patients were compared with 40 age- and sex-matched healthy subjects (22 males and 18 females) enrolled as controls with median age 10.8 (IQR, 5 – 14.9) years.
Patients were subjected to full medical history taking and thorough clinical examination with special emphasis on disease duration and hepatic or neurological manifestations as well as enzyme replacement therapy. Laboratory investigations included CBC, bone marrow examination, liver and kidney function tests and PGRN levels measured by enzyme linked immunosorbent assay (ELISA). Initial β-glucosidase and chitotriosidase levels as well as molecular analysis of the GBA gene were obtained from medical records of patients. Severity score index was calculated. Radiological examination included abdominal ultrasonography to assess the volume of liver and spleen in cubic cm (calculated as multiples of normal sizes predicted for body weight) and TE for assessment of liver stiffness.
In the current work, the most common GBA genotype among the studied patients was homozygous C1448T>C being found in 33 (64.7%) of patients (6 had type 1 and 27 had type 2) while 5 patients had heterozygous C1448T>C, 4 (7.8%) patients had homozygous C1226A>G genotype, 3 (5.9%) patients had C475C>T; 1226A>G mutations and 2 (3.9%) patients had homozygous C1342G>C GBA genotype.
By TE, the mean liver stiffness among GD patients was 6.76 ± 1.9 Kpa and 14 (27.5%) GD patients had significant fibrosis (F2 stage or higher). Liver stiffness was significantly higher in type 1 GD patients than type 3 and in splenectomized patients as well as those with dysphagia. Liver stiffness was positively correlated to liver volume and age of onset of ERT. These variables remain significant in multivariable regression analysis.
PGRN levels in GD patients were significantly lower compared with healthy controls. PGRN was significantly lower in GD patients with squint, dysphagia and significant fibrosis by TE than those without. PGRN was positively correlated to white blood cell count and hemoglobin while it was negatively correlated to severity score index, liver volume and liver stiffness. Severity score index, hemoglobin and liver stiffness were the significant independent variables related to increased PGRN levels by multivariable regression analysis.