What every physician needs to know:
Gaucher disease is an inborn error of metabolism in the family of lysosomal storage diseases due to a deficiency of glucocerebrosidase (acid beta-glucosidase [GBA or GCase]). As a result, the substrate (glucosylceramide or glucocerebroside which is a component of cell membranes) accumulates in the macrophages of the bone, liver, spleen and more rarely lungs, kidneys and brain.
Are you sure your patient has Gaucher disease? What should you expect to find?
Because of the excess storage of glucosylceramide, there is the potential for significant bone and bone marrow disease, hepatosplenomegaly, anemia and thrombocytopenia. Patients complain of fatigue, bruising, bone pain, and children can experience growth retardation. Significant morbidity can result, leading to aseptic necrosis of bone, bone infarcts (which can cause bone crises), pathological fractures, portal and pulmonary hypertension.
Beware of other conditions that can mimic Gaucher disease:
Because of the anemia, thrombocytopenia and splenomegaly, the differential diagnosis includes: leukemia, lymphoma, infectious diseases, hemoglobinopathies, infestations such as leishmaniasis and other storage diseases such as Niemann-Pick disease.
Which individuals are most at risk for developing Gaucher disease:
The disease is due to mutations of a gene located on chromosome 1 q21. More than 300 distinct GCase mutations have been identified, of which about 80% are single nucleotide substitutions.
About 70% of patients are of Ashkenazi Jewish descent with a carrier rate of 1/15 to 1/18 and incidence of 1/600 to 1/800. The worldwide incidence is approximately 1/75,000 births.
There are three types of Gaucher disease:
Type 1 disease has been considered non-neuronopathic
Type 2 patients have severe neurological consequences and is lethal by 1 to 2 years
Type 3 disease has the onset of neurological signs in the first or second decades and life expectancy of 20 to 30 years.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
Gaucher disease in the past was diagnosed by bone marrow examination. However, this is unnecessary today, since enzymatic diagnosis can be made on peripheral blood leucocytes. Similarly, molecular diagnosis can also be made on peripheral blood with the most common gene mutations N370S, L444P, 84gg, and IVS2(+1).
Additional studies should include a complete blood count, chemistries and liver panel. Surrogate markers, which are lysosomal enzymes, which include tartrate resistant acid phosphatase, angiotensin-converting enzyme and chitotrosidase, can be used to corroborate the diagnosis and to follow treatment.
What imaging studies (if any) will be helpful in making or excluding the diagnosis of Gaucher disease?
Imaging studies are a very important, not only for diagnostic purposes, but also for monitoring the course of the disease. Performing a magnetic resonance imaging (MRI) scan or computed tomography (CT) imaging of the liver and spleen, utilizing volumetric measurements of these organs, is of critical importance.
Plain films of the spine and femurs can be used for comparisons. The femur can show the Erlenmeyer flask deformity which is characteristic of the disease and is a result of impaired bone remodeling during growth. MRI’s of the femurs can show critical bone findings such as aseptic necrosis and a moth-eaten appearance, and dual-energy X-ray absorptiometry (DXA) scans (bone density) can identify under-mineralization which is a useful marker of disease activity.
If you decide the patient has Gaucher disease, what therapies should you initiate immediately?
Therapeutic goals include: improving symptoms, preventing irreversible organ disease, and preventing growth retardation in children. If it is determined that treatment is necessary, enzyme replacement therapy (ERT) with either imiglucerase, velaglucerase, or taliglucarase should be initiated.
Those with more severe disease may need blood transfusions and narcotic analgesics, but the effects for most patients are transient.
For those intolerant of enzyme (which is rare) or who decline it, substrate reduction therapy with the oral agent miglustat can be considered.
More definitive therapies?
The dosing of ERT should be based on the severity of disease and can vary from 30 to 60 units/kg every 2 weeks by intravenous infusion. By analyzing thousands of patients in the Gaucher Registry, therapeutic goals have been established. The majority of patients show dramatic improvement by 2 years in the hematological parameters and hepatosplenomegaly. Bone findings improve more slowly.
Dosage reductions or increases can be made as warranted. With substrate reduction therapy, the improvements are more modest. The initial dose of Miglustat is 100mg tid.
A newer oral agent, eliglustat, a glucocerebroside synthase inhibitor, appears very promising in clinical trials.
What other therapies are helpful for reducing complications?
Bisphosphonates have been shown to augment the effect of ERT on bone mineral density, but it is not clear what the duration of these should be. Pain management may be of importance for some patients too.
What should you tell the patient and the family about prognosis?
The prognosis of Gaucher type 1 with ERT is good with the symptoms and signs of the disease improving progressively. Even beyond 5 years, there is continued evidence of improvement. The most recent data from the Gaucher Registry suggests life expectancy may be shortened slightly.
There is an increased risk of multiple myeloma in type 1 patients as there also is an increased risk of Parkinsonism. The latter finding may dispel the notion that type 1 Gaucher disease is non-neuronopathic.
Patients with type 3 disease have improvement of their disease with ERT except for neurological findings and have a life span of 20 to 30 years.
Those with type 2 disease die in infancy and currently therapy is not advised except for symptomatic measures. Studies with oral agents, which are substrate reduction agents, which are small molecules and can cross the blood brain barrier, may help neurological complications, but this needs further study.
"What if" scenarios.
One of the most common problems in managing Gaucher disease is under dosing of ERT, which can lead to persistence of bone symptoms and progression of bone disease, even in the face of improving hematogical values and organ volumes. Additionally, any severe pain should be considered a “bone crisis” (usually from a bone infarct) or a pathological fracture, which will need to be managed with appropriate analgesics , IV fluids, imaging studies and hospitalization if necessary and surgery if warranted.
Aseptic necrosis of the femur or humerus can ultimately lead to severe degenerative joint disease and joint replacement, although with early intervention with ERT, the latter can be prevented. Paradoxically, some patients with mild hepatosplenomegaly and hematological findings may have severe bone disease, so bone imaging is essential.
Deficiency of GBA leads to the accumulation of glucosylceramide and other glycolipids in the lysosomes of the macrophage. As a result, tissue levels increase significantly and the hallmark cell, the Gaucher cell, can easily be identified in sites such as the bone marrow, liver and spleen. There is evidence that cytokines are released and other inciters of inflammation which can lead to tissue damage. In the bone, decreased mineral density and marrow dysfunction occurs ultimately leading to bone infarcts, aseptic necrosis, pathological fractures and poor bone remodeling.
In the liver, fibrosis can occur and cirrhosis may be an end result, and the spleen enlarges and sequesters platelets, so thrombocytopenia is common. Therefore, patients can present with hepatosplenomegaly, anemia, thrombocytopenia, bruising and bleeding, bone and joint pain, and growth retardation. In neuronopathic forms, they can have strabismus, supranuclear gaze palsy, dementia, corneal opacities and hydrops fetalis as a result of central nervous system involvement.
The family of lysosomal storage diseases are predominantly autosomal recessive including Gaucher disease, but a few are X-linked such as Fabry disease. The organs effected depend upon which enzyme is deficient. For example, the sphingolipidoses include Gaucher disease, Tay-Sachs, and Fabry disease; the mucopolysaccharidoses (MPS) such as Hurler syndrome, and the glycogenoses which includes Pompe disease. ERT is currently available for Gaucher disease, Fabry disease, Pompe disease, and Hunter syndrome (MPS II).
What other clinical manifestations may help me to diagnose Gaucher disease?
Patients with Gaucher disease can vary in their symptomatology from no symptoms at all, to those with fatigue, bone pain, abdominal distension, and bruising. Children with neuronopathic subtypes are usually diagnosed early on because Gaucher disease is in the differential diagnosis for these children. Otherwise, physical examination can show pallor, purpura, hepatosplenomegaly, short stature, and more rarely, hyperpigmented skin lesions.
What other additional laboratory studies may be ordered?
Because of the higher risk of multiple myeloma, it is advised that a yearly serum immunoelectrophoresis be performed in adults. In those patients showing a paraprotein, greater vigilance should be maintained. If the quantitative level of a paraprotein is rising , then a bone marrow examination should be considered.
What’s the evidence?
Cox, T, Lachmann, R, Hollak, C. “Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease the substrate biosynthesis”. . vol. 355. 2000. pp. 1481-1485. [This was the seminal report regarding the agent miglustat showing its efficacy as an oral agent for the treatment of Gaucher disease.]
Grabowski, G, Kolodny, E, Weinreb, N, Valle, D, Beaudet, AL, Vogelstein, B. “Gaucher disease”. Metabolic and Molecular Bases of Inherited Disease. 2010. [These two chapters represent the most comprehensive reviews of Gaucher dsiease. The chapter designated 146.1 is derived from the International Cooperative Gaucher Group-Gaucher Registry data base.]
Pastores, GM, Weinreb, NJ, Aerts, H. “Therapeutic goals in the treatment of Gaucher disease”. . vol. 41. 2004. pp. 4-14. [This review summarizes all the available data regarding treating with enzyme replacement and establishes guidelines for expected responses to treatment and when dosing can be appropriately reduced.]
Rosenbloom, B, Balwani, M, Bronstein, JM. “The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry”. . vol. 46. 2011. pp. 95-102. [This paper reports that there is a significantly increased risk of developing Parkinsonism, at an earlier age than de novo Parkinson's, in patients with Gaucher disease, which confirms and expands upon the available prior studies in the literature. There is also an increase risk of Parkinson's in Gaucher carriers.]
Rosenbloom, BE, Weinreb, NJ, Zimran, A. “Gaucher disease and cancer incidence: a study from the Gaucher Registry”. . vol. 105. 2005. pp. 4569-4572. [This study clearly shows that the concerns for increased cancer risk in Gaucher disease is real and especially for multiple myeloma where the risk is increase 6 fold.]
Weinreb, NJ, Charrow, J, Andersson, HC. “Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry”. . vol. 113. 2002. pp. 112-119. [This was the first study in their literature showing the short- and long-term benefits of enyzyme replacement therapy for Gaucher disease.]
Wenger, DA, Coppola, S, Liu, SL. “Insights into the diagnosis and treatment of lysomal storage diseases”. . vol. 60. 2003. pp. 322-328. [This paper describes those lysosomal storage diseases with neurological aspects, and especially types 2 and 3 Gaucher disease.]
Lukina, E, Watman, N, Arreguin, EA. “Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease Type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study”. . vol. 116. 2010. pp. 4905-8. (This study and subsequent reports of this new agent show it to be non-inferior to enzyme replacement therapy.)
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- Gaucher disease
- What every physician needs to know:
- Are you sure your patient has Gaucher disease? What should you expect to find?
- Beware of other conditions that can mimic Gaucher disease:
- Which individuals are most at risk for developing Gaucher disease:
- What imaging studies (if any) will be helpful in making or excluding the diagnosis of Gaucher disease?
- If you decide the patient has Gaucher disease, what therapies should you initiate immediately?
- More definitive therapies?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- "What if" scenarios.
- What other clinical manifestations may help me to diagnose Gaucher disease?
- What other additional laboratory studies may be ordered?
- What’s the evidence?