Medical Care
Enzyme replacement
Enzyme replacement therapy (ERT) for type 1 Gaucher disease includes imiglucerase (Cerezyme), velaglucerase alfa (VPRIV), and taliglucerase alfa (Elelyso). Historically, most patients received the recombinant enzyme imiglucerase. [12] 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 dose of 15-60 U/kg, with a standard adult dose being around 30 U/kg. Good responses have been described with all dose regimens, and the issue of the most suitable initial and maintenance dosages remains controversial.
ERT 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 ERT 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 ERT 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.
Glucosylceramide synthase inhibitors
Glucosylceramide synthase inhibitors include miglustat (Zavesca) and eliglustat (Cerdelga). Miglustat was approved in 2003 as monotherapy for treatment of adults with mild-to-moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. Patients have reported mild to moderate adverse effects with miglustat, the most frequently reported being GI upset.
Eliglustat was approved in August 2014 as first-line treatment for the long-term treatment of adults with Gaucher disease type 1. The dose of eliglustat is determined by establishing the patient’s CYP2D6 phenotype (ie, extensive metabolizers [EM], intermediate metabolizers [IM], or poor metabolizers [PM]).
Approval was based on efficacy data from 2 positive phase 3 studies involving 199 patients. One study involved patients new to therapy (trial 1), and the other involved patients switching from approved enzyme replacement therapies (trial 2). Efficacy data from 4 years of the Cerdelga phase 2 study also contributed to the approval. Improvements in study participants were observed in spleen size, platelet levels, hemoglobin levels, and liver volume, and noninferiority to enzyme replacement therapy (imiglucerase) was established in trial 2. [13, 14]
In a study of 159 patients with Gaucher disease, researchers found that fewer patients treated with eliglustat (85%) than imiglucerase (94%) met criteria for hemoglobin level, platelet count, spleen volume, and liver volume indicating stable disease for 12 months. Adverse events were more common with eliglustat, but most were mild.
In three other studies, eliglustat was superior to placebo over nine months of treatment, outcomes were similar for patients treated with eliglustat or imiglucerase for 4 years, and outcomes of eliglustat treatment were similar when dosing regimens were determined based on CYP2D6-genotype-predicted phenotype or plasma eliglustat concentrations. [15]
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:
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Medical geneticist
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Hematologist
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Orthopedist
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Neurologist
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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.
Prevention
Gaucher disease is inherited as an autosomal recessive trait. While it is panethnic, Gaucher disease is more common in individuals of Ashkenazi Jewish. Although carrier-screening programs in this population have been established at some centers to identify couples at risk for having a child affected with Gaucher disease, testing must be offered in conjunction with genetic counseling to provide couples at risk, even asymptomatic individuals, with a description of the range of associated phenotypes and their options, which include prenatal diagnosis.
Newborn screening is not performed for Gaucher disease.
Long-Term Monitoring
Most symptomatic patients with Gaucher disease receive enzyme replacement therapy (ERT), which is provided on an outpatient basis. [7] Monitoring for allergic reactions is essential.
Monitoring patients who receive taliglucerase or miglustat (Zavesca) every 6 months is recommended.
Patients with osteoporosis have responded favorably to bisphosphonates.
Patients not currently on therapy should be monitored at regular intervals for changes in organ size and/or hemoglobin and platelet counts.
Further Inpatient Care
Patients with Gaucher disease who have bone crises may require admission for pain relief. Patients with severe hematologic manifestations may have episodes of bleeding that require inpatient treatment. Children with type 2 Gaucher disease are often hospitalized with failure to thrive or aspiration pneumonias.
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Autosomal recessive inheritance pattern.
