INTRODUCTION — Gaucher disease (GD) is an inborn error of metabolism that affects the recycling of cellular glycolipids. It results from deficiency of a lysosomal enzyme glucocerebrosidase (also known as glucosylceramide or acid beta-glucosidase [GBA]). Glucosylceramide (also called glucocerebroside) and several related compounds that ordinarily are degraded to glucose and lipid components by glucocerebrosidase accumulate within the lysosomes of cells in patients with GD [1].

Treatment of GD is tailored to the individual patient because of the variability in the manifestations, severity, and progression of the disease [2,3]. GD is one of the few inherited metabolic disorders for which enzyme-replacement therapy (ERT) is available [4,5]. Additional therapies include substrate-reduction therapy (SRT) and supportive care measures to manage associated conditions.

The treatment of GD is discussed here. The pathogenesis, genetics, clinical manifestations, diagnosis, initial assessment, and routine monitoring are discussed separately. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Gaucher disease: Initial assessment, monitoring, and prognosis".)

THERAPEUTIC GOALS — The basic goals of treatment are elimination or improvement of symptoms, prevention of irreversible complications, and improvement in the overall health and quality of life [6-9]. An additional goal in children is optimization of growth. An international panel of clinicians with extensive clinical experience in GD has developed a list of therapeutic goals for use as guides for optimal treatment (table 1 and table 2 and table 3). Regular monitoring is performed to assess the response to therapy, make adjustments when goals are not met, and ensure the maintenance of achieved goals (table 4). The goal of minimal disease activity, based upon the three major systemic domains involved (hematologic, visceral, and skeletal), is another possible treatment target [10]. The frequency of reevaluation depends upon disease severity and should be assessed on an individual basis [11]. (See "Gaucher disease: Initial assessment, monitoring, and prognosis".)

Visceral, hematologic, skeletal, and other aspects of nonneuronopathic disease are considered separately since each of these components is relatively independent of the others with respect to disease burden and response to therapy [7]. Skeletal manifestations are associated with the greatest morbidity and, once present, are among the least responsive to enzyme-replacement therapy (ERT). ERT may slow or prevent progression of skeletal complications, but osteonecrosis, osteosclerosis, and vertebral compression are irreversible. Early treatment may prevent or lessen the severity of these complications, and therefore, early identification is crucial to improving ultimate outcome [12,13]. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)

ENZYME-REPLACEMENT THERAPY — The decision to offer Gaucher-specific therapy (enzyme-replacement therapy [ERT] or substrate-reduction therapy [SRT]) in patients with nonneuronopathic GD (type 1 Gaucher disease [GD1]) is based upon disease severity, as determined by the initial assessment, or significant disease progression, as demonstrated through regular follow-up. ERT with a recombinant glucocerebrosidase (imiglucerase, velaglucerase alfa, or taliglucerase alpha; the last is not approved for use in the European Union) or SRT with eliglustat are the preferred treatments for patients with clinically significant manifestations of nonneuronopathic GD (GD1). ERT with imiglucerase or velaglucerase (off-label use) is also an option in patients with chronic neuronopathic GD (type 3 [GD3]) who have visceral manifestations and in patients at risk for GD3, but it is not suitable for patients with acute neuronopathic GD (type 2 [GD2]) (table 5) [6,14-20]. (See 'Substrate-reduction therapy' below.)

Clinical trials conducted in the late 1980s and early 1990s demonstrated the efficacy of ERT in patients with GD1 who were treated with glucocerebrosidase prepared from human placenta [21,22]. The advance that was critical to the success of this technique was molecular targeting of the enzyme to tissue macrophages via mannose receptors expressed by these cells. A recombinant preparation has been available since 1993. (See 'Preparation' below.)

Indications — Published guidelines for ERT treatment in children and adults with GD were developed by consensus of international experts, using data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry and local experience [6,11,12,15,23].

ERT with imiglucerase, velaglucerase, or taliglucerase according to local approvals (taliglucerase is not approved in the European Union) is indicated for the following patients with nonneuronopathic (GD1) disease [12,24,25]:

●Symptomatic children (including those with malnutrition, growth retardation, impaired psychomotor development, and/or fatigue) [7,25] since early presentation is associated with more severe disease [7].

●Adult patients with symptomatic disease (eg, platelet count <60,000/microL, liver >2.5 times normal size, spleen >15 times normal size, radiologic evidence of skeletal disease).

The implementation of therapy and evaluation of response vary depending upon the initial assessment (table 4) and individualized therapeutic goals (table 1 and table 2 and table 3) [6].

The European Working Group on Gaucher Disease has formulated consensus guidelines for the treatment of neuronopathic GD [26,27]. These recommendations are summarized in the table (table 5). In brief, ERT with imiglucerase should be considered for patients with GD3 disease and severe visceral symptoms [24,28]. In addition, it should be offered in patients at risk for GD3 neuronopathic GD [26] due to genotype or family history who are identified early in the disease course, before the onset of neurologic signs or symptoms. ERT may also have palliative effects on visceral manifestations in GD2 disease, but it does not alter the fatal neurologic outcome and therefore is generally not used [27,29,30].

Preparation — Imiglucerase is produced by recombinant DNA technology in a Chinese hamster ovary cell system, velaglucerase alfa by gene activation technology in a human cell line, and taliglucerase alpha by a novel plant cell-based protein expression system [17-20,31-33]. The purified enzyme imiglucerase is a monomeric glycoprotein composed of 497 amino acids. Recombinant enzyme differs from the native form and the therapeutic placental form (alglucerase) by a histidine for arginine amino acid substitution at position 495 [34]. Oligosaccharide chains at the glycosylation sites are modified by sequential deglycosylation [35] to terminate in mannose moieties. Mannose groups are specifically recognized by endocytic receptors, allowing uptake of the enzyme by the cell and trafficking to the lysosome. Velaglucerase differs from imiglucerase insomuch as the enzyme protein sequence is the native human sequence and greater mannose display is achieved. Kifunensine, a mannosidase I inhibitor, is used in the medium during production to obtain the desired glycosylation profile. The inhibition of the natural maturation of the glycans generates predominantly high mannose-type oligosaccharides [32]. The taliglucerase platform uses genetically modified carrot cells. Terminal paucimannosidic type N-glycans are achieved by targeting to the plant storage vacuoles, where the terminal residues are normally removed [36].

Administration

Initiation — The initial dose is determined for the individual patient and depends upon age at presentation, the site(s) and extent of involvement, and the presence of irreversible pathology [6,25,37]. The usual starting dose for patients with GD1 is between 30 and 60 units/kg, administered intravenously over one to two hours every two weeks. The minimum recommended starting dose for children is 30 units/kg every two weeks [12,25]. The typical starting dose used for imiglucerase in GD3 is 60 units/kg.

Large, prospective trials comparing dose regimens have not been performed. Initial doses of 30 to 60 int. units/kg for imiglucerase and taliglucerase and 60 int. units/kg for velaglucerase [17-20], given every two weeks, were safe and effective in improving visceral and bone marrow disease and quality of life in patients with GD1 [16,22,38-40]. Progression of skeletal disease leading to irreversible skeletal damage has occurred in some patients treated with lower doses despite improvement in other parameters [41]. In addition, results from a retrospective study of registry patients suggest a dose response in bone mineral density improvement [42].

Long-term outcomes of ERT with imiglucerase at two centers using low-dose (median dose 15 to 30 units/kg every four weeks) and high-dose (median dose 80 units/kg every four weeks) treatment protocols in adult patients were compared retrospectively [43]. Improvement in hemoglobin, platelet count, and hepatosplenomegaly was not significantly different between cohorts. Patients at the center using high-dose ERT had more rapid improvement in plasma chitotriosidase (a marker of alternative-type macrophage activation that is overexpressed in Gaucher cells) and bone marrow involvement as measured by magnetic resonance imaging (MRI). (See "Gaucher disease: Initial assessment, monitoring, and prognosis", section on 'Laboratory evaluation' and "Gaucher disease: Initial assessment, monitoring, and prognosis", section on 'Routine monitoring'.)

Modifications — Dose adjustments are made on an individual basis. Generally, patients with GD1 do not require more than 60 int. units/kg every other week. The mean dose used for long-term therapy in the United States and Germany is approximately 30 int. units/kg every two weeks (range 30 to 60 int. units/kg) [25] but is lower in the United Kingdom, Netherlands, and Israel, for example (approximately 25 int. units/kg every other week, sometimes less) [43].

●Dose increases – Increases in dose may be necessary to achieve therapeutic goals or for relapse following dose reduction [6]. The dose should be increased by 50 percent, for example, if bone crises continue [44]. An increased dose may also be indicated if visceromegaly, anemia, thrombocytopenia, and biomarkers fail to improve after six months [12]. However, an increased dose is unlikely to reverse certain types of pathology (eg, osteonecrosis and fibrosis of the liver, spleen, or lung). Additional evaluation may be necessary for patients who are unable to achieve their therapeutic goals after three to six months. (See "Gaucher disease: Initial assessment, monitoring, and prognosis".)

●Dose reductions – Decisions regarding dose reduction should be made with caution [12]. Dose reductions should only be considered after all relevant therapeutic goals have been met [6]. Dose reductions must be accompanied by reassessment of disease severity (table 1 and table 2 and table 3) to ensure the maintenance of therapeutic goals (table 4).

●Treatment interruptions – Treatment is continued throughout the patient's life. Prolonged treatment interruptions are not recommended, because there are several reports of disease progression if this occurs [45-51]. Patients in whom interruptions of therapy are unavoidable require close monitoring during the time of discontinuation [6]. Major problems in the production and supply of imiglucerase in 2009 and 2010 led to a six-month shortage, resulting in interruption of treatment and dose reduction. This six-month interruption in treatment was associated with an increase in fatigue, generally modest falls in platelet count, increases in biomarkers, and occasional episodes of irreversible bone events [52-54].

Effectiveness

Nonneuronopathic — Although there is limited direct and published evidence from head-to-head studies, the available evidence suggests that all the ERTs are approximately equivalent in efficacy [16-20,22,55]. Response to treatment varies from patient to patient, but analysis of data from the Gaucher Registry and GD treatment centers demonstrates certain trends for imiglucerase and alglucerase in patients with nonneuronopathic (GD1) disease [22,25,56-62]:

●Anemia – Hemoglobin concentrations typically increase to normal or near-normal levels within 6 to 12 months [56,60], with a sustained response throughout five years [60].

●Thrombocytopenia – Patients with intact spleens usually have the greatest response within two years and have slower improvement thereafter [60]. These patients have a smaller response if baseline thrombocytopenia is severe. Approximately one-quarter of patients still have thrombocytopenia (platelet count <120 x 10⁹/L), with severe-persistent thrombocytopenia (platelet count <60 x 10⁹/L) seen in 2 percent of patients after four to five years of therapy [59]. Predictors for persistent thrombocytopenia include very low baseline platelet count and increased baseline splenic volume. Platelet counts return to normal in 6 to 12 months in the rare splenectomized patients with thrombocytopenia due to marrow failure [60].

●Visceral disease – Reduction in spleen and liver volumes usually occurs within six months after initiation [56]. Hepatomegaly and splenomegaly decrease by up to 60 percent, but spleen volume may remain more than five times normal in some patients [60].

●Skeletal disease – Skeletal improvement may not be evident until after two to three years of therapy [22,25,57]. Bone mineralization may stabilize and slowly improve, and the risk of pathologic fracture may be reduced [58]. Symptoms resolved in 52 percent of patients with bone pain in one series, and no further episodes occurred in 94 percent of those who suffered bone crises before treatment [60].

●Other – Reduction in fatigue is usually seen within six months of onset of therapy [56].

Treating children with ERT may mitigate or prevent the complications that occur later in life, particularly skeletal abnormalities [7,44,63-65]. Long-term ERT was associated with normalization or near normalization of height, hemoglobin level, platelet count, liver and spleen volume, and bone mineral density among 884 children registered in the Gaucher Registry [64].

A systematic review and pooled analysis of observational studies of ERT (imiglucerase) in adults found that the lumbar spine fat fraction approximately doubled compared with baseline measurements [66]. The percentage of responders to ERT based upon an increase in MRI T1-weighted signal and decrease in bone marrow infiltration ranged from 63 to 75 percent. The MRI bone marrow burden score also decreased after treatment (weighted mean difference [WMD] -4.98; 95% CI -8.38 to -1.57). However, there was not a significant increase in bone mineral density, as measured by lumbar spine and femur Z-scores, after ERT.

A small, open-label, phase-I/II study of velaglucerase showed similar results to historical imiglucerase data [17-20,67]. All five therapeutic goals (anemia, thrombocytopenia, hepatomegaly, splenomegaly, and skeletal pathology) were met in all patients (8 out of the original 12) who reached four years of treatment and were on a reduced dose for at least two years. The efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients were demonstrated in a nine-month, global, randomized, noninferiority study comparing velaglucerase alfa with imiglucerase (60 int. units/kg every other week) in treatment-naïve patients aged 3 to 73 years with anemia and either thrombocytopenia or organomegaly [18].

Neuronopathic — Guidelines for the use of ERT in patients with neuronopathic GD are less well established. The recombinant enzyme does not cross the blood-brain barrier and therefore has limited ability to impact central nervous system (CNS) disease. However, other somatic effects of GD should respond to ERT [28,29]. In some studies, ERT was found to reverse almost all of the systemic manifestations and appeared to stabilize or slow progression of central neurologic disease (except progressive myoclonic epilepsy) in some patients, despite the fact that the drug does not cross the blood-brain barrier [68-71]. This was illustrated in a series of 21 patients, ages 8 months to 35 years, with GD3 who were treated with individually adjusted doses of enzyme and followed for two to eight years [69]:

●Improvement occurred in hemoglobin levels, platelet count, and acid phosphatase values.

●Spleen and liver volume decreased, and bone structure improved.

●Asymptomatic interstitial lung disease, present in 19 patients, did not respond to treatment.

●Neurologic responses were variable:

•Supranuclear gaze palsy was unchanged in 19 patients, improved in 1, and worsened in 1.

•Auditory brainstem response (ABR) improved in 2 patients, was unchanged in 17, and deteriorated in 2. In another report, all eight children receiving high-dose ERT had deterioration in ABR [72].

In pregnancy — Published [73] and original data from several large treatment centers were summarized in a comprehensive review of ERT for GD during pregnancy [74]. Pregnancy in GD may be complicated by deterioration in hematologic disease, organomegaly, and bone involvement. Previously undiagnosed GD often comes to medical attention as a result. Data suggest a reduced risk of spontaneous abortion in women treated with alglucerase and/or imiglucerase and reduced risk of Gaucher-related complications during delivery and the postpartum period. There was no report of any untoward effects of alglucerase and/or imiglucerase on the fetus or on breastfed infants of treated mothers.

Adverse effects — ERT for GD is generally well tolerated [40,75]. The side effects are usually related to the intravenous infusion and include fever, chills, and flu-like symptoms [75]. The mechanism is thought to be immune related but not immunoglobulin E (IgE) mediated. Acute IgE-mediated reactions are rare. When they occur, symptoms may include pruritus, flushing, urticaria/angioedema, chest discomfort, respiratory symptoms, cyanosis, and hypotension. ERT can be continued in most patients. In difficult cases, the infusion rate should be reduced and antihistamines and/or glucocorticoids given before the infusion [25]. Variable rate of anti-drug antibody formation due to treatment have been reported (15, 1, and 14 to 53 percent, for imiglucerase, velaglucerase, and taliglucerase, respectively).

Approximately 13 to 15 percent of treated patients develop immunoglobulin G (IgG) antibody to the enzyme [24,75-77]. Many of these patients stop producing antibody after two to three years of therapy [76]. The development of antibody is occasionally associated with diminished effectiveness of ERT and/or clinical deterioration [78,79]. However, such events are infrequent. In clinical trials of velaglucerase alfa, for example, 1 of 94 patients developed IgG-neutralizing antibodies to the enzyme. No infusion-related reactions were reported for this patient. No patients developed IgE antibodies to the enzyme. Reports of anti-drug antibodies to taliglucerase alfa range from 14 percent, in patients switched from imiglucerase, to 53 percent, in patients previously naïve to enzyme replacement [80].

Monitoring — Routine monitoring of disease activity should be carried out during ERT. Monitoring should be in accordance with at least the minimum recommendations for effective monitoring of patients provided by the International Collaborative Gaucher Group (ICGG) [11]. The recommended monitoring tests and schedule are discussed in detail separately (table 4). (See "Gaucher disease: Initial assessment, monitoring, and prognosis", section on 'Routine monitoring'.)

Patients who do not achieve their therapeutic goals should undergo evaluation for confounding factors (eg, poor compliance with therapy; development of comorbid conditions, such as malignancy or immune thrombocytopenia; or development of neutralizing antibody). The additional evaluation varies depending upon the goal that is not achieved.

Routine monitoring for the development IgG antibodies to the enzyme is not recommended, since it is an uncommon event. A pretreatment sample should routinely be drawn and stored. Subsequent samples should be drawn and tested (in parallel with the stored baseline sample) if clinically indicated, for example, if infusion reactions occur or if there is a suspicion of diminished efficacy of treatment. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and 'Adverse effects' above.)

SUBSTRATE-REDUCTION THERAPY — Substrate-reduction therapy (SRT), which reduces glycolipid accumulation by decreasing the synthesis of glucocerebroside, the substrate of the deficient enzyme, is an alternative to enzyme-replacement therapy (ERT) for some adult patients [15,81-86]. Eliglustat is approved for a broader range of use than miglustat.

Eliglustat was approved in the United States in 2014 and the European Union in 2015 as a first-line treatment for adults with type 1 GD (GD1) [87,88]. Dosing of eliglustat is based upon patient CYP2D6 (cytochrome P450, subfamily IID, polypeptide 6) metabolizer status. The dose for extensive and intermediate metabolizers is 84 mg orally twice daily and for poor metabolizers is 84 mg once daily. Eliglustat is not indicated in patients who are CYP2D6 ultra-rapid metabolizers, since they may not achieve adequate concentrations of eliglustat to achieve a therapeutic effect. Concomitant use of CYP2D6 and CYP3A inhibitors is contraindicated. The most common strong and moderate inhibitors are listed in the tables (table 6 and table 7), but other drug interactions are possible. For specific interactions, use the Lexicomp drug interactions program included with UpToDate.

Miglustat (N-butyldeoxynojirimycin), an alternative SRT, is approved in the United States for restricted use in adults with GD who are medically unable to receive ERT [89] and in Europe for symptomatic adult patients with mild to moderate disease in whom ERT is unsuitable (eg, venous access is problematic or the patient has a history of a severe infusion reaction) [90]. Miglustat was also evaluated as a maintenance therapy for patients whose disease had stabilized during treatment with imiglucerase and was found to maintain clinical stability in some patients [91]. The recommended dose of miglustat is 100 mg orally three times per day [92]. Miglustat is contraindicated in pregnancy and in men and women wishing to start a family due to the potential for causing birth defects and infertility [93].

In a randomized trial of 40 previously untreated adults with GD1 and baseline splenomegaly and thrombocytopenia, treatment with eliglustat (50 or 100 mg orally twice daily) for nine months lead to greater improvements in spleen and liver volume, platelet count, and hemoglobin level compared with placebo [94].

Adults with GD1 treated with ERT for at least three years who had stable disease were randomly assigned 2:1 to receive oral eliglustat (n = 106) twice daily or intravenous imiglucerase (n = 54) every other week for 12 months in a phase-III, open-label, noninferiority study [95]. Eliglustat was noninferior to imiglucerase, with a between-group difference of -8.8 percent (95% CI -17.6 to 4.2) in the composite endpoint of decreased hematologic measurements (hemoglobin and platelet count) and increased organ volume (spleen and liver). These findings suggest that eliglustat can be used as first-line or maintenance therapy in adult patients with GD1.

Studies of miglustat have only shown modest improvements in mean liver and spleen volumes and slight changes in hemoglobin levels and platelet counts (increased in therapy-naïve patients and decreased in those who had previously received ERT) [81,92,96-98]. In addition, miglustat does not appear to have significant benefits on certain neurologic manifestations of type 3 GD (GD3) despite its ability to cross the blood-brain barrier. [99]. The use of miglustat is therefore only indicated for adult GD1 patients with mild to moderate GD who cannot receive ERT.

Side effects of miglustat treatment include diarrhea (79 percent of patients in one study), weight loss, tremor, and peripheral neuropathy [81,96]. These adverse effects are usually reversed by reducing the dose or discontinuing the drug. They also diminish with longer use. Patients treated with miglustat should be monitored for emergent neuropathy. Gastrointestinal side effects may also improve with dietary modifications and/or antidiarrheal medications [100]. Patients on eliglustat should be monitored for possible drug interactions due to poor drug metabolism related to cytochrome P450 2D6 (CYP2D6) activity. For specific interactions, use the Lexicomp drug interactions program included with UpToDate.

OTHER TREATMENT OPTIONS

Splenectomy — The availability of enzyme-replacement therapy (ERT) has limited the indications for splenectomy. It is primarily performed if other measures fail to control life-threatening thrombocytopenia with high risk of bleeding. Other possible indications include unremitting abdominal pain caused by recurrent splenic infarction, severe restrictive pulmonary disease, inferior vena cava syndrome, or inability to receive ERT or substrate-reduction therapy (SRT) [101]. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Visceral disease'.)

Before ERT was available, splenectomy was performed to improve thrombocytopenia and anemia. Partial splenectomy was sometimes performed to minimize the risk of overwhelming sepsis with total splenectomy. However, partial splenectomy had limited success and was associated with serious complications, including accelerated bone destruction, regrowth of the splenic remnant with recurrence of symptoms [101], and more rapid central nervous system (CNS) deterioration in patients with type 3a (Norrbottnian) disease [102]. Total splenectomy was associated with a worse bone outcome than partial splenectomy in another series of patients [103]. It is uncertain whether bony deterioration is a direct result of splenectomy, but one study has documented a strong temporal relationship between splenectomy and subsequent episodes of avascular necrosis [65].

Specific precautions must be taken to prevent sepsis in patients who require splenectomy. These are discussed separately. (See "Prevention of infection in patients with impaired splenic function".)

Hematopoietic stem cell transplantation — Hematopoietic stem cell transplantation (HSCT or HCT) can provide a definitive cure for GD [104-106]. However, this procedure is associated with substantial morbidity and mortality and therefore has been effectively replaced by ERT and SRT in clinical practice [107,108]. HSCT is still considered in patients at risk for neuronopathic GD who present prior to the onset of neurologic signs or symptoms.

Gene therapy — Future treatment of GD may include gene therapy. In an animal model, gene therapy through retroviral transduction of bone marrow from mice with type 1 GD (GD1) both prevented the development of GD and corrected an established GD phenotype [109]. In mice with established GD, gene therapy resulted in normalization of glucosylceramide concentrations and resolution of Gaucher cell infiltration of bone marrow, spleen, and liver five to six months after transplantation [109].

In humans, retroviral vector transfer of the glucocerebrosidase gene into cultured bone marrow cells from patients with GD resulted in expression of physiologic levels of enzyme [110]. However, efforts to accomplish this in the clinical setting have been unsuccessful because of the low efficiency of gene delivery into hematopoietic stem cells.

Enzyme-enhancement therapy — Enzyme-enhancement therapy (EET), which attempts to increase the residual function of mutant enzymes, is another potential future therapy for GD [24]. In EET, pharmacologic or chemical chaperones are used to stabilize folding of mutant glucocerebrosidase [111-114] or decrease its degradation [115]. Chemical chaperones for the treatment of GD have been evaluated in clinical trials, but the development program of the lead compound GD (afegostat tartrate) was suspended as a result of lack of efficacy [116].

Ambroxol, a mucolytic agent that is not available in the United States but is used in other countries, has been proposed as a candidate pharmacologic chaperone. In an open-label pilot study, five patients with neuronopathic GD received high-dose oral ambroxol in combination with ERT. Patients on this combination therapy significantly increased lymphocyte glucocerebrosidase activity and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction improved in all patients. Relief from myoclonus led to recovery of gross motor function in two patients who subsequently regained walking ability [117].

SUPPORTIVE CARE — Supportive care measures are necessary to manage bone disease, bleeding tendency, and other associated conditions (eg, Parkinsonism). Management also includes addressing the psychosocial needs of the patient [118].

Skeletal disease — The treatment of bone disease is directed toward the prevention of irreversible complications, such as avascular necrosis [24].

●The possibility of osteomyelitis should be considered during episodes of bone pain since delayed diagnosis of osteomyelitis is associated with increased morbidity [119]. Blood cultures, imaging studies (ie, radionuclide scan, magnetic resonance imaging [MRI]), and/or bone biopsies and cultures should be obtained, as warranted. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis".)

●Bone pain crises can be ameliorated by intravenous fluids and analgesia. Options for analgesia include acetaminophen and nonsteroidal anti-inflammatory agents [12]. Narcotics may be necessary for severe crises but are not effective in all patients [120]. Oral prednisolone (20 mg/m² per day) may be helpful in such patients.

●Alendronate and other bisphosphonate drugs [14] are a potential adjunctive therapy for adult patients whose osteopenia is refractory to enzyme-replacement therapy (ERT), although they do not address the underlying defect causing the bone disease. In a controlled trial, patients who were treated with alendronate for 18 months had increased lumbar bone mineral density compared with controls [121]. Long bone radiographs showed no change in focal lesions or bone deformities in either group.

●Orthopedic procedures, such as hip replacement, may improve the quality of life. However, the success of these procedures is sometimes limited by the cortical thinning that frequently is present. Four patients at one center had successful total hip replacement with uncemented components at least one year after onset of ERT [122]. The bone beyond the osteonecrotic areas was noted to have a normal appearance and consistency at the time of surgery in these patients. These procedures should be undertaken at centers experienced with surgical management of metabolic bone disease. Findings from one series suggest that use of ERT at any time improves outcomes for total hip replacements [123].

Bleeding tendency — Patients with GD have an increased risk of bleeding because of thrombocytopenia, defective platelet function, and/or coagulation factor abnormalities. They require appropriate evaluation and preparation before surgical procedures or pregnancy [6,24]. (See "Approach to the adult with a suspected bleeding disorder" and "Approach to the child with bleeding symptoms" and "Preoperative assessment of hemostasis" and "Overview of the etiology and evaluation of vaginal bleeding in pregnancy".)

Neuronopathic disease — Supportive care is necessary for the neurologic disease in patients with type 2 GD (GD2) or type 3 GD (GD3) [24] This is usually best delivered under the care of an experienced (usually pediatric) neurologist. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Aspiration due to swallowing dysfunction in children" and "Symptomatic (secondary) myoclonus".)

Other complications — Patients with GD and clinical features of Parkinson disease (PD) are managed the same as other patients with PD. (See "Nonpharmacologic management of Parkinson disease" and "Initial pharmacologic treatment of Parkinson disease".)

Similarly, patients with hematologic malignancies are normally referred to an oncologist or hematologist. (See appropriate topic reviews on lymphoma, leukemia, and multiple myeloma.)

Patients with severe liver disease and hepatopulmonary syndrome may require liver transplantation [124,125]. (See "Hepatopulmonary syndrome in adults: Prevalence, causes, clinical manifestations, and diagnosis" and "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gaucher disease".)

SUMMARY AND RECOMMENDATIONS

●The basic goals of treatment of Gaucher disease (GD) are elimination of symptoms, prevention of irreversible complications, and improvement in the overall health and quality of life. An additional goal in children is optimization of growth and development. Treatment of GD is tailored to the individual patient because of the variability in the manifestations, severity, and progression of the disease. An international panel of clinicians with extensive clinical experience in GD has developed a list of therapeutic goals to be used as guides for optimal individualized treatment (table 1 and table 2 and table 3). (See 'Therapeutic goals' above.)

●The decision to offer enzyme-replacement therapy (ERT) or substrate-reduction therapy (SRT) in nonneuronopathic (type 1) GD (GD1) is based upon disease severity, as determined by the initial assessment, or significant disease progression, as demonstrated through regular follow-up (table 4). We recommend ERT with recombinant glucocerebrosidases (imiglucerase, velaglucerase alfa, or taliglucerase) for all symptomatic children and for patients with severe manifestations of nonneuronopathic GD1 (Grade 1B). SRT with eliglustat is a suitable alternative for adults with symptomatic disease and suitable metabolizer status. (See 'Indications' above and 'Nonneuronopathic' above.)

●Treatment options for adult patients with GD1 include SRT with eliglustat or ERT. The choice is likely to be largely based upon patient preference. Dosing of eliglustat is determined by metabolizer status. A small number of adult patients who metabolize eliglustat more quickly or at an undetermined rate are not eligible for treatment with this drug. SRT with miglustat, an inhibitor of glucosylceramide synthase, is an option in adult patients with mild to moderate GD1 who are unwilling or unable to receive ERT. The recommended dose of miglustat is 100 mg orally three times per day. Patients treated with miglustat should be monitored for emergent neuropathy. (See 'Substrate-reduction therapy' above and 'Enzyme-replacement therapy' above.)

●We suggest ERT for patients with neuronopathic type 3 disease and severe visceral symptoms (Grade 2B). In addition, we suggest ERT in patients at risk for neuronopathic type 3 GD (GD3) due to genotype or family history who are identified early in the disease course, before the onset of neurologic signs or symptoms (Grade 2C). We suggest not administering ERT in patients with type 2 disease (Grade 2C). ERT may have palliative effects on visceral manifestations in patients with type 2 disease, but it does not alter the fatal neurologic outcome. (See 'Indications' above and 'Neuronopathic' above.)

●ERT is individualized. Factors considered in choosing the initial dose include age at presentation, comorbid conditions, the site(s) and extent of involvement, and the presence of irreversible pathology. For most patients, we use an initial dose of 30 to 60 int. units/kg intravenously every two weeks. The minimum recommended starting dose for children is 30 int. units/kg. Treatment response varies, but, in general, improvements occur within six months after initiation of therapy and include reduction of spleen and liver volumes, resolution of thrombocytopenia and anemia, and reduction in fatigue. Improvement in skeletal disease may not be evident for two to three years. (See 'Administration' above.)

●Routine monitoring of disease activity is performed during ERT (table 4). Dose adjustments are made on an individual basis. We advise increasing the dose if visceromegaly, anemia, thrombocytopenia, and biomarkers fail to improve after six months or if the patient fails to achieve specific therapeutic goals. We advise increasing the dose by 50 percent if bone crises continue. We suggest that dose reductions be considered only after all relevant therapeutic goals have been met. Dose reductions must be accompanied by reassessment of disease severity to ensure the maintenance of therapeutic goals. Treatment is continued throughout the patient's life. Treatment interruptions are not recommended. (See 'Administration' above and "Gaucher disease: Initial assessment, monitoring, and prognosis".)

●The availability and efficacy of ERT have limited the indications for splenectomy and hematopoietic cell transplantation (HSCT). Splenectomy is indicated if other measures fail to control life-threatening thrombocytopenia. Bone marrow transplantation may be an option in patients known to be at-risk for neuronopathic disease who present early in the disease course. (See 'Other treatment options' above.)

DISCLOSURE — The author of this topic has the following disclosures that may be relevant to this topic: Honoraria for speaking and advisory boards from Genzyme, Shire, and Protalix (lysosomal diseases), and research and travel grants from Genzyme and Shire.

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Patrick Deegan, MD, MRCPI, FRCP, who contributed to an earlier version of this topic review.