eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Gaucher Disease: Treatment & Medication
Updated: Oct 16, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Enzyme replacement therapy (ERT) for Gaucher disease is now available, with most patients receiving recombinant enzyme (imiglucerase [Cerezyme]).2 This preparation is highly effective in reversing the visceral and hematologic manifestations of Gaucher disease. However, skeletal disease is slow to respond, and pulmonary involvement is relatively resistant to the enzyme. Treatment is typically administered once every other week at a high dose, but, in some patients, treatment is administered every week at a medium dose or as many as 3 times per week at low doses. Good responses have been described with all dose regimens, and the issue of the most suitable initial and maintenance dosages remains controversial.
ERT with imiglucerase is indicated for patients with type 1 Gaucher disease who exhibit clinical signs and symptoms of the disease, including anemia, thrombocytopenia, skeletal disease, or visceromegaly. Severity and rate of disease progression widely varies, especially in adults, which makes treatment decisions extremely difficult in some patients. Generally, children who present symptomatically, rather than because of family history, may have severe disease manifestations that require early treatment. Presymptomatic treatment with imiglucerase remains controversial because of the lack of prognostic correlation between genotype and disease severity and the high cost of the therapy.
For most patients with Gaucher disease in the United States, treatment with Cerezyme is typically guided by a geneticist or a hematologist. Patients should receive periodic follow-up at a center familiar with Gaucher disease, if possible.
ERT has a remarkable effect on hepatosplenomegaly, with an average overall decrease of 25% in liver and spleen volume after 6 months of therapy. In most patients with anemia, hemoglobin levels rise by 1.5 g/dL during the first 4-6 months of therapy. An additional increase of 1 g/dL is observed in the subsequent 9-18 months in patients with persistent anemia. The platelet count responds more slowly, doubling on average over 1 year. The hematologic status of patients with splenomegaly must be closely monitored, and splenectomy is still occasionally necessary.
Skeletal disease is the slowest to respond, with symptomatic improvement described by some within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response. Patients with bone crises require pain relief, hydration, and close monitoring. A bone scan is sometimes needed to differentiate between a bone crisis and infection.
Other effects of ERT in children with Gaucher disease include an increased growth velocity, weight gain, increased energy levels, and a correction of both delayed puberty and hypermetabolic state.
The response of patients to ERT widely varies and does not correlate with genotype, disease severity, splenectomy, or age. However, a number of factors, including cirrhosis and portal hypertension, extensive infarction and fibrosis of the spleen, and lung involvement, portend a poor response to therapy.
The symptoms of patients with Gaucher disease who have associated hematologic malignancies respond relatively poorly to ERT. To overcome these difficulties, increased dosage and frequency of enzyme infusions have been attempted. The symptoms of patients with decompensated liver disease do not appear to respond well to ERT, and these patients remain at risk for life-threatening hemorrhage due to variceal bleeding.
No evidence shows that ERT results in neurologic improvement. Although the enzyme affects the visceral involvement in types 2 and 3 disease, the associated brain involvement may persist or progress.
Surgical Care
Partial and total splenectomy was once advocated in the treatment of patients with Gaucher disease. However, with the availability of ERT, this procedure is no longer necessary in most patients.
In addition, patients with Gaucher disease may require hip replacements or other orthopedic procedures to treat skeletal disease. This is best undertaken after the patient has undergone several months of ERT.
Consultations
Consultations with the following specialists are indicated:
- Medical geneticist
- Hematologist
- Orthopedist
- Neurologist
- Neuro-ophthalmologist
Diet
No dietary manipulation has been found to affect disease progression.
Activity
Patients with massive splenomegaly or severe thrombocytopenia should avoid contact sports and any other activities that place them at risk for splenic rupture or bleeding
Medication
Two therapies have been approved by the US Food and Drug Administration (FDA) for the treatment of Gaucher disease. Enzyme replacement therapy (ERT) with glucocerebrosidase purified from human placenta was FDA approved in 1991, followed by approval in 1994 of a recombinant form of the enzyme produced in cultured Chinese hamster ovary (CHO) cells. Worldwide, over 4,000 patients with Gaucher disease have received ERT, which is safe and well tolerated.
Approximately 10-15% of patients with Gaucher disease develop antibodies to the enzyme protein, but few develop any significant allergic reactions, which are controlled with premedication with hydrocortisone, antihistamines, or both. All antibodies have immunoglobulin G (IgG), mostly of the IgG1 subclass. A few patients with Gaucher disease have developed antibodies that impair enzyme activity.
Oral substrate reduction therapy, using an aminosugar inhibitor of glucosylceramide synthase, has been approved for use in patients with type 1 Gaucher disease in whom ERT is not a therapeutic option because of allergy, hypersensitivity, or poor venous access. Although oral substrate reduction therapy was approved by the FDA in 2003, long-term data regarding efficacy and safety are not yet available.
Enzyme replacement therapy
In most cases, ERT is highly effective in reversing the visceral and hematologic manifestations of Gaucher disease. Recombinant beta-glucocerebrosidase (imiglucerase [Cerezyme]) has replaced the original tissue-derived product, alglucerase (Ceredase), which is no longer marketed. Presymptomatic use is controversial because of the high cost and the extremely variable clinical course.
Imiglucerase (Cerezyme)
A recombinant-derived analog of beta-glucocerebrosidase produced in mammalian cell culture and chemically modified by mannose termination of glycosylated amino acids. Catalyzes hydrolytic cleavage of glucocerebroside (a glycoprotein) to glucose and ceramide within the lysosomes of phagocytic cells in the reticuloendothelial system. Treatment with recombinant enzyme improves anemia and thrombocytopenia, reduces spleen and liver size, and decreases cachexia
Adult
30-150 U/kg IV qmo typically; dose must be individualized and widely varies; initial dose may range from 2.5 U/kg 3 times/wk to 60 U/kg q2wk
Dilute in 0.9% NaCl and infuse over 1-2 h
Pediatric
Administer as in adults
None reported
Documented hypersensitivity
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
May develop IgG antibodies (15%) and hypersensitivity (6-7%); allergic reactions easily controlled with premedication with hydrocortisone, antihistamines, or both; may cause nausea, abdominal pain, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia; may cause pruritus at injection site
Glucosylceramide synthase inhibitors:
These agents inhibit the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions that result in the synthesis of most glycosphingolipids, including glucocerebroside. The goal of treatment is to reduce the rate of glucocerebroside biosynthesis so that the amount is reduced to a level that allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy).
Miglustat (Zavesca)
Indicated for type 1 Gaucher disease in patients in whom ERT is not a therapeutic option. Reduces GSL production by inhibiting glucosylceramide synthase. Reduces spleen and liver volume and increases hemoglobin and platelet counts.
Adult
100 mg PO tid
In patients with renal impairment, dosage should be reduced as follows:
CrCl 50-70 mL/min: 100 mg PO bid
CrCl 30-50 mL/min: 100 mg PO qd
CrCl <30 mL/min: Not recommended
Pediatric
<18 years: Not established
Limited data exist; none reported
Documented hypersensitivity; severe renal impairment
Pregnancy
X - Contraindicated in pregnancy
Precautions
Caution in renal impairment (decrease dose); neurological monitoring for possible peripheral neuropathy q6mo is indicated; may cause tremor (30%); diarrhea and weight loss are common (85% and 65%, respectively); adversely affects spermatogenesis; use reliable contraceptive method and maintain for 3 mo after discontinuing drug
More on Gaucher Disease |
| Overview: Gaucher Disease |
| Differential Diagnoses & Workup: Gaucher Disease |
 Treatment & Medication: Gaucher Disease |
| Follow-up: Gaucher Disease |
| Multimedia: Gaucher Disease |
| References |
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Further Reading
Keywords
Gaucher disease, Gaucher’s disease, glucocerebrosidase deficiency, cerebroside lipidosis, acid beta-glucosidase deficiency, splenomegaly, anemia, lipid storage disease, lysosomal storage disease, glucocerebrosidase, glucosylceramidase, GBA, pancytopenia, massive hepatosplenomegaly, diffuse infiltrative pulmonary disease, parkinsonism, Lewy body
