Gaucher cell in bone marrow cytology | Humpath.com. (2017). Gaucher disease - Humpath.com - Human pathology. [online] Available at: http://www.humpath.com/spip.php?article1034 [Accessed 22 May 2017]
Contents
Deficiency of the lysosomal enzyme glucocerebrosidase (β-glucosidase), leading to the accumulation of glucocerebroside within tissue macrophages in multiple organs.
M/C lysosomal storage disease (in India & worldwide)
Subgroup, sphingolipidosis as it involves dysfunctional metabolism of sphingolipids
Autosomal recessive inheritance (GBA gene on chromosome 1)
History
Philippe Charles Ernest Gaucher (July 26, 1854 – January 25, 1918), physician and scientist from France
Philippe Charles Ernest Gaucher (July 26, 1854 – January 25, 1918), physician and scientist from France
The disease was first recognized by the French doctor Philippe Gaucher, who originally described it in 1882 and lent his name to the condition. In 1902, its mode of inheritance was discovered by Nathan Brill. The neuronal damage associated with the disease was discovered in the 1920s, and the biochemical basis for the disease was elucidated in the 1960s by Roscoe Brady. The first effective treatment for the disease, the drug alglucerase (Ceredase), was approved by the FDA in April 1991. An improved drug, imiglucerase (Cerezyme), was approved by the FDA in May 1994 and has replaced the use of Ceredase. October is National Gaucher’s Disease Awareness Month in the United States.
Pathophysiology
GBA gene (Chromosome 1) Autosomal recessive inheritance ↓ ↓ glucocerebrosidase/acid β-glucosidase (GBA) ↓ Glucocerebroside (component of cell membrane) Cannot be broken → accumulates in macrophage lysosomes ↓ Gaucher cells (crumpled-tissue paper appearance) ↓ Lysosomal enzymes & inflammatory cytokines (released by gaucher cells & nearby macrophages d/t unclear mechanism) ↓ Immune response ↓ Scar tissue
Hydrolysis of glucosylceramide (GlcCer) by glucocerebrosidase (GCase) in the lysosome (A). GCase is activated by saposin C. In lysosomal storage diseases, an enzyme deficiency is responsible for the accumulation of its substrate in the cell lysosome (overload disease). Gaucher disease is caused by a deficiency in glucocerebrosidase (GCase) (or β-glucosidase), which leads to an accumulation of GlcCer. GlcCer forms fibrillar aggregates that accumulate in macrophages and result in the cell cytoplasm presenting a characteristic “crumpled tissue paper” appearance (B), personal pictures, with the courtesy of Fabrice Camou and Rachid Seddik). These cells, known as Gaucher cells, infiltrate various organs (e.g., bone marrow, spleen, and liver) and are responsible for the major signs of the disease. | Stirnemann, J., Belmatoug, N., Camou, F., Serratrice, C., Froissart, R., Caillaud, C., … Berger, M. G. (2017). A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. International Journal of Molecular Sciences, 18(2), 441. https://doi.org/10.3390/ijms18020441
Gaucher cells localised in:
Bone marrow
Liver
Spleen
Histopathology:
No role for histological examination of the bone marrow, liver or spleen for diagnosis of the disease.
Micrograph showing crinkled paper macrophages in the marrow space in a case of Gaucher disease, H&E stain. | Nephron – CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15306996Photomicrograph of a Gaucher cell (arrows) with “crumpled tissue paper” cytoplasm and eccentric nucleus on Hematoxylin and Eosin staining. | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005
Presentation
Presentation
Clinical spectrum:
Type 1 GD (GD1): Non-neuronopathic GD (M/C)
Type 2 GD (GD2): Acute neuronopathic/infantile cerebral GD (1% cases)
Type 3 GD (GD3): Chronic neuronopathic GD (5% cases)
Clinical classification of the forms of GD. Recently the classic categories of types 1, 2 and 3 have blurry edges along a phenotypic continuum. Patients with GD can have a spectrum of symptoms, ranging from mild to severe neurological effects. | Linari, S., & Castaman, G. (2015). Clinical manifestations and management of Gaucher disease. Clinical Cases in Mineral and Bone Metabolism : The Official Journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases, 12(2), 157–164. https://doi.org/10.11138/ccmbm/2015.12.2.157
Type 1
Type 2
Type 3
Disease onset
Childhood/adulthood
Infancy
Childhood/adolescence
Splenohepatomegaly
Present
Present
Present
High prevalence
Ashkenazi Jews
?
Swedish province of Norrbotten
Bone involvement
Present
Absent
Present
Ocular signs
Absent
Present
Present
Neurological involvement
Absent
Present, severe
Present, mild
Other organ involvement
Liver cirrhosis Pulmonary hypertension
Hydrops Congenital ichthyosis
Cardiac and vascular calcifications
Lifespan with or without therapy
Early childhood to late adulthood
Less than 2 years
Variable—up to early adulthood
Response to ERT
Good
Poor, not indicated
Variable
Haematological (classical) symptoms:
Painless hepatosplenomegaly
Hypersplenism & pancytopenia
Osteoporosis (75% cases)
Erlenmeyer flask deformity of femur (aseptic necrosis of the femur head)
Bone pain (mild-to-moderate intermittent pain)
Severe acute “bone crises”
Accompanied by periosteal elevation, leukocytosis, and fever and can cause debilitation for several days and require narcotic analgesics
Strabismus in a 2-year-old child with Type 3 Gaucher disease. | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005Severe kyphosis and chest deformity in a 10-year-old child with Type 1 Gaucher disease. | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005Massive splenohepatomegaly in a 18-month-old child with Type 1 Gaucher disease. | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005
Neurological symptoms:
GD1: Impaired olfaction and cognition
GD2: Serious convulsions, hypertonia, intellectual disability, and apnea
GD3: Myoclonus, convulsions, dementia, and ocular muscle apraxia
Prevalence of affected organ involvement in Gaucher disease among children at diagnosis. Growth retardation refers to patients below the fifth percentile for height. Radiologic evidence of bone disease may indicate Erlenmeyer flask deformity, marrow infiltration, osteopenia, avascular necrosis, infarction, and/or new fractures. Anemia is defined according to age and sex references for hemoglobin concentrations as follows: less than 11 g/dL for boys 12 years and older; less than 10 g/dL for girls 12 years and older; less than 9.5 g/dL for children aged 2 to younger than 12 years; less than 8.5 for children aged 6 months to younger than 2 years; and less than 9.1 g/dL for infants younger than 6 months. Hepatomegaly (liver volume in multiples of normal size predicted for body weight [MN]) is defined as moderate (>1.25 to 2.5 MN) to severe (>2.5 MN). Splenomegaly (spleen volume in multiples of normal) is defined as moderate (>5 to 15 MN) to severe (>15 MN). Thrombocytopenia is defined as moderate (platelet count, 60 × 103/μL to >120 × 103/μL) to severe (platelet count, <60 × 103/μL). | Kaplan, P., HC, A., KA, K., & JD, Y. (2006). The clinical and demographic characteristics of nonneuronopathic gaucher disease in 887 children at diagnosis. Archives of Pediatrics & Adolescent Medicine, 160(6), 603–608. Retrieved from http://dx.doi.org/10.1001/archpedi.160.6.603
Diagnosis
Glucocerebrosidase assay (GOLD STANDARD):
Measures glucocerebrosidase activity in leukocytes (or fibroblasts)
CT-scan:
Contrast enhanced CT scan of liver reveals ill-defined minimally enhancing hypodensity in segment 7 of the liver with portal and hepatic venous branches are seen coursing through this lesion (arrows) This represent hepatic infiltration by Gaucher cells. (Gaucheroma). | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005Enlarged abdominal lymph nodes with calcification (arrows) on CT scan. | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005
X-ray:
X-ray of the Erlenmeyer Flask deformity of the femora—showing lack of curve at the dia-metaphyseal junction resembling a conical flask (picture to the right) along with cortical thinning. | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005
MRI:
T1 and T2W1 images of the lumbar spine reveals generalized decrease in marrow signal (arrows) in the vertebral bodies representing changes of osteosclerosis. | Nagral, A. (2014). Gaucher disease. Journal of Clinical and Experimental Hepatology, 4(1), 37–50. https://doi.org/10.1016/j.jceh.2014.02.005
Management
Treatment strategies in a patient with Gaucher disease | Modified from: Ho M.W., Seck J., Schmidt D. Adult Gaucher’s disease: kindred studies and demonstration of a deficiency of acid beta-glucosidase in cultured fibroblasts. Am J Hum Genet. 1972;24:37–45.
