A reappraisal of Gaucher disease—diagnosis and disease management algorithms

Type 1 (non-neuronopathic) Gaucher disease was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed and it has become a prototype for treatments for related orphan diseases. There are currently four treatment options available to patients with Gaucher disease, nevertheless, almost 25% of Type 1 Gaucher patients do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. Diagnosis of Gaucher disease by enzyme testing is unequivocal, but the rarity of the disease and nonspecific and heterogeneous nature of Gaucher disease symptoms may impede consideration of this disease in the differential diagnosis. To help promote timely diagnosis and optimal management of the protean presentations of Gaucher disease, a consensus meeting was convened to develop algorithms for diagnosis and disease management for Gaucher disease. The defect in Gaucher disease is an inherited deficiency of the lysosomal enzyme acid β-glucosidase (glucocerebrosidase, GBA1), which results in the accumulation of glucocerebroside within lysosomes of macrophages. Systemic accumulation of these glycolipid-lipid engorged cells (eponymously known as Gaucher cells, Fig. 1) results in variable combinations of splenomegaly with associated abdominal discomfort; anemia associated with chronic fatigue; bleeding due to thrombocytopenia and/or Gaucher disease-related coagulopathy; hepatomegaly, abnormal tests of liver function; and a diverse pattern of bone disease 1. Increased susceptibility to infections may result from impaired neutrophil function and neutropenia 2. Rarely, the lungs, lymphatic system, skin, eyes, kidneys, and the heart are involved and, in the rare neuronopathic forms, neurodegenerative disease results 1. Gaucher disease is traditionally classified into three broad phenotypic categories: Type 1 (non-neuronopathic disease); Type 2, fulminant neuronopathic disease that is fatal during infancy; and Type 3, chronic neuronopathic disease, that usually results in death in childhood or early adult life 1. Further distinct phenotypic categories may be recognized within these broad groups. Bone marrow smear and biopsy from a patient with N370S homozygous Gaucher disease showing classical striated macrophages and marrow replacement. Smear: Gaucher cells (×100). Core: bone marrow replacement by Gaucher cells (×20). Type 1 (non-neuronopathic) Gaucher disease accounts for more than 90% all Gaucher disease patients. Its prevalence world wide is 1 in 50,000 to 100,000 but it is as high as ∼1 in 850 in individuals of Ashkenazi heritage 3-6. The broadest phenotypic spectrum in Gaucher disease with respect to age of onset, rate of progression, and organs affected occurs in Type 1 Gaucher disease 7. Homozygosity for the N370S mutation is the most common genotype in the Ashkenazim in whom it accounts for ∼70% of all disease alleles. It is associated with atypical presentation in adults or the older patient and is notable for significant skeletal disease despite inconspicuous classical manifestations (splenomegaly, hepatomegaly, anemia, and thrombocytopenia). However, severe disease with classic manifestations presenting in childhood may occur in a minority of N370S homozygous patients 8, 9. The most common disease allele of GBA1 world wide is L444P mutation, which occurs in the sequence of the closely linked pseudogene; it is believed that gene conversion events lead to L444P mutation in the active gene. It seems likely that the most frequent genotype of Type 1 Gaucher disease in populations of European descent in the world is N370S/L444P. Generally this genotype leads to more severe disease compared with N370S homozygosity 1, 10, 11 (Figs. 2 and 3). Relationship between age of presentation at extent of splenomegaly (determined by volumetric MRI with normal spleen volume at 0.2% body weight; extent of splenomegaly is indicated by multiple of normal, i.e. ×N). Three most common genotypes in North American Gaucher disease patient populations are depicted: N370S/N370S, N370S/L444P, and N370S/84G ins G). The results show that the majority of older N370S homozygous patients harbor no, or minimal, splenomegaly). (a and b). Comparison of severity of hepatomegaly and bone disease (Herman score 9) in patients with intact spleen and those with prior splenectomy stratified for GBA1 gene genotype. The numbers of patients are depicted at the bottom of the bars. Treatment with macrophage-targeted mannose-terminated glucocerebrosidase enzyme replacement therapy (imiglucerase, Cerezyme®, Genzyme Corporation, Cambridge, MA) is the standard of care for Type 1 Gaucher disease and of non-neuronopathic manifestations of Type 3 Gaucher disease. Evidence from the ICGG Gaucher Registry, indicates that enzyme replacement with imiglucerase and its predecessor alglucerase reverses hematological and visceral manifestations of the disease 12 and reduces the bone marrow burden of Gaucher cells resulting in amelioration of osteopenia, bone pain, risk of bone crises and overall improvement in quality of life 13-16. Several aspects of bone disease, such as osteonecrosis, osteofibrosis, and lytic lesions cannot be reversed but timely initiation of enzyme therapy reduces the risk of these irreversible complications 8, 17. Other variants of macrophage-targeted enzyme replacement therapies are undergoing clinical trials: velaglucerase, a human fibroblast-derived enzyme, was recently approved for treatment of Type 1 Gaucher disease 18 and taliglucerase, a plant derived enzyme is in clinical trials 19. Substrate reduction therapy (Zavesca® miglustat, Actelion Pharmaceuticals, Allschwil, Switzerland) is approved for patients with mild Gaucher disease who are unable to receive enzyme replacement therapy 20, 21. A more specific and potent inhibitor of glucosylceramide synthesis, eliglustat tartrate is currently in Phase 3 trials having shown impressive efficacy and safety in Phase 2 trials 22, 23. Prompt diagnosis before the occurrence of irreversible complications underpins the Gaucher disease management model 24. The early symptoms of Type 1 Gaucher disease tend to reflect the hematological aspects of the disease (splenomegaly, anemia, thrombocytopenia, and bleeding tendency) 25. Patients with Gaucher disease, therefore, are most likely to be referred to hematologists for diagnosis and management. However, only ∼20% of hematologists/oncologists in one study considered Gaucher disease in differential diagnoses even in the presence of all classical symptoms 8. Diagnosis may be achieved in high-risk groups, such as individuals of Ashkenazi Jewish ancestry, by opportunistic screening (i.e., those with any of the manifestations of Gaucher disease or those with surrogate indicators of disease, i.e, severe osteoporosis, hyperferritinemia, gallstones, and low HDL cholesterol) and family screening after diagnosis in a family member 26. The aim of the consensus meeting was to develop algorithms for diagnosis and management based on current understanding of the full clinical spectrum of presentations of Gaucher disease. The authors' combined experience of 362 patients with Gaucher disease revealed a consistent pattern of previous misdiagnoses that included leukemia, immune thrombocytopenia purpura, autoimmune disease, hepatic cirrhosis, idiopathic avascular necrosis, viral disease, idiopathic splenomegaly, and anemia of chronic disease. Misdiagnosis led to complications such as avascular necrosis, osteopenia, liver disease, and bleeding complications and inappropriate procedures such as splenectomy, liver biopsy, and empirical corticosteroid therapy (see Appendix). Malignancy is commonly the first diagnosis entertained in patients who are eventually diagnosed with Gaucher disease 8, 27. Interestingly, the first patient ever described with Gaucher disease by Dr Philippe Gaucher in 1882 was believed to harbor malignancy affecting the spleen. In one study, the diagnosis most frequently considered was hematologic malignancy (leukemia 65%, lymphoma 36%, multiple myeloma 22%, chronic granulocytic leukemia 14%) 8. It should be noted that the risk of hematological malignancies in Gaucher disease is increased, especially of multiple myeloma 9, 28-31. The life-time risk of multiple myeloma in Gaucher disease is higher than 25-fold compared with the general population 9, 29-32. In patients of Ashkenazi ancestry, the frequency of Gaucher disease is ∼1 in 800 while hematologic malignancies are much less frequent at ∼1 in 2,500 33. Therefore, in this ethnic group, it is prudent to test for Gaucher disease as a first-line investigation, in any patient presenting with splenomegaly and cytopenia. It is important to keep in mind that the most common genotype in this ethnic group, homozygosity for N370S mutation is often characterized by mild cytopenia and splenomegaly that escape initial detection. Therefore, presence of conditions associated with Gaucher disease should alert the clinician, i.e., hyperferritinemia, low HDL cholesterol, premature gallstones or osteoporosis, and gammopathy. In the non-Ashkenazi populations Gaucher disease is markedly less frequent (∼1 in 40,000) compared with hematologic malignancies. In this setting, it would be appropriate to consider Gaucher disease in the differential diagnosis after malignancies have been ruled out. In this setting, bone marrow biopsy is usually performed; it should become routine to search for Gaucher cells as well as for evidence of hematological malignancies. The above considerations form the rationale for the diagnostic algorithm stratified by ethnicity (Figs. 4 and 5). Portal hypertension due to advanced liver disease from well-known etiologies must be ruled out before application of the algorithm. Diagnosis algorithm for individuals of Ashkenazi origin. Diagnosis of Gaucher disease should be considered in any individual of Ashkenazi Jewish ancestry presenting with mild, moderate or severe splenomegaly. When splenomegaly is absent, Gaucher disease should be considered in the presence of thrombocytopenia (even if mild), bleeding tendency, unexplained stable hyperferritinemia with normal transferrin saturation, or increased inflammatory markers. *In patients with bleeding diatheses, coagulopathies such as factor XI deficiency common in Askenazim 34 should be excluded. Diagnostic algorithm for individuals of non-Ashkenazi Jewish origin. Compared with Gaucher disease, malignancy is likely to be the more frequent cause of splenomegaly in this population. In this setting it is reasonable to perform bone marrow biopsy in initial investigations. The finding of Gaucher cells in bone marrow aspirate will suggest Gaucher disease although Gaucher disease and malignancy are not mutually exclusive. Pseudo-Gaucher cells have also been observed in malignant conditions in the absence of Gaucher disease 35. In developing these diagnostic algorithms, the authors focused on splenomegaly, as a key presenting sign since it is present in the vast majority of Gaucher patients 10. In the ICGG Registry 87% of patients have splenomegaly in excess of five times normal (median spleen volume = 15.2 × normal) 6. However, Gaucher disease may occur without splenomegaly and the absence of splenomegaly does not exclude Gaucher disease (Fig. 2). This is often the case in older adults homozygous for the N370S mutation in whom splenomegaly is mild and may not be present 9. Splenomegaly is defined precisely by volumetric measurement of the spleen by MRI, CT or ultrasound scanning followed by conversion to weight (1 mL equals 1 gm) as multiple of the normal spleen size, i.e., 0.2% body weight 36. Splenectomy in patients with Gaucher disease is associated with aggressive disease in the liver, skeleton, and the lungs 37 (Fig. 3). Therefore, it should become mandatory to test for Gaucher disease in any patient being considered for splenectomy when the cause of splenomegaly has not been established. Assessment of splenomegaly in Gaucher disease should be combined with an examination of spleen parenchyma. There is almost 20% incidence of focal splenic defects in Gaucher disease and its incidence increases with increasing spleen size 38. These lesions may represent focal collections of Gaucher cells or areas of infarction and have been a source of misdiagnosis as splenic neoplasms. The diagnostic test for Gaucher disease is the demonstration of low acid β-glucosidase activity in peripheral blood leukocytes (normal range 2.1–5.3 μmol/l/hr) 39. The assay is performed in blood leukocytes using a fluorescent substrate, 4-methyumbelliferone β-glucoside. The test requires 10 mL EDTA blood sample shipped at ambient temperature by overnight delivery to the lab. Molecular analysis of GBA1 gene is complicated by presence of highly homologous pseudogene that harbors several mutations, which if present in the active gene leads to Gaucher disease. A number of techniques have been developed to circumvent potential problems arising from this situation in order to analyze only the active gene sequences uncontaminated by pseudogene sequences 40. A negative screen for common GBA1 mutations does not exclude Gaucher disease (see Discussion). Therefore, undertaking sequencing of the entire coding region of GBA1 gene is recommended in patients strongly suspected of harboring Gaucher disease when a screen for common mutations is negative 40. Mutation analysis of the GBA1 gene may provide some prognostic information although there is considerable variation of disease severity among patients harboring an identical GBA1 genotype 7 (Fig. 2). Knowledge of the GBA1 mutation in a proband also facilitates family screening for genetic counseling purposes since heterozygote carriers cannot be reliably identified by enzyme assays. Routine bone marrow examination is not necessary for diagnosis. It has been discouraged in the diagnosis of Gaucher disease, due to availability of less invasive and robust enzymatic test and the fact that it may cause bleeding complications due to thrombocytopenia and coagulopathy. Many patients report having had this procedure usually before Gaucher disease had been considered. Care should be exercised in the interpretation of bone marrow samples as false-negative results are common especially upon examination of bone marrow aspirate as opposed to bone marrow biopsy. Conversely, the presence of pseudo-Gaucher cells may lead to erroneous diagnosis 35. Pseudo-Gaucher cells have been found in diverse conditions such as multiple myeloma 41, myelodysplasia and myelodysplastic syndromes 42, chronic myeloid leukemia 43, pulmonary tuberculosis 44, mycobacterioses 45, and sickle cell disease 46. Occasionally bone marrow biopsy may be indicated in a patient with Gaucher disease suspected of a superimposed hematologic disorder, i.e., myelofibrosis, multiple myeloma, or other hematologic malignancy. Several serum proteins are consistently elevated in Gaucher disease, with some being used as biomarkers for routine monitoring, i.e., angiotensin-converting enzyme (ACE), tartrate-resistant acid phosphatase (TRAP), chitotriosidase, and a chemokine, CCL18 47, 48. The finding of elevated levels of one or more of these markers is never sufficient to diagnose Gaucher disease since these markers may be elevated in other Other are common in Gaucher disease, such as low low serum and and elevated 9, a diagnosis of Gaucher disease is the should be on of all disease (Fig. to disease to for enzyme replacement and to develop and of life and a severity score using one of the that are in the are of in treatment skeletal is especially important since it is the of most irreversible which occur without of neuronopathic Gaucher disease has been described In non-neuronopathic disease examination should also a search for symptoms and of and peripheral (see Discussion). A in the management and of Gaucher disease is that it is a chronic disease that is at variable and leads to [9, treatment and to the manifestations of Gaucher disease are based on the experience with alglucerase and imiglucerase enzyme replacement therapy which is a for all other treatment Assessment of to treatment is derived from a body of evidence The heterogeneous and chronic nature of Type 1 Gaucher disease requires an disease management model with respect to enzyme and in disease be achieved by therapy before irreversible complications occur compared with a It is that there is a for imiglucerase therapy Therefore, for patients in whom disease is a i.e., moderate to severe disease those with complications such as and pulmonary the initial of imiglucerase is usually body weight in a Patients may to after initial disease (Fig. In patients with such as pulmonary enzyme therapy followed by other appropriate therapy should be adult patients with less severe disease, initial of body is a prudent patients may not treatment because have mild or even disease such patients are usually of N370S homozygous genotype. These patients should be to of disease that treatment be before symptoms or irreversible occurs (Fig. It is important to that patients may be harbor significant disease manifestations such as splenomegaly, and These patients should receive treatment to disease and algorithm. of patients therapy imiglucerase as have been a may be with to that disease does not Treatment must be one treatment will all patients. The diagnosis and management algorithms are likely to be to the majority of patients with Gaucher disease despite there being more than mutations in the GBA1 gene that to vast phenotypic mutations ins 2 and for of disease in patients of Ashkenazi Jewish ancestry and in patients of non-Ashkenazi descent [1. In the most disease genotype is the homozygous being associated with severe childhood onset and a high risk of 1, 10, There is phenotypic among patients with GBA1 genotype as well as among affected (Fig. 2). is only in by GBA1 gene mutations and the important of has been but Gaucher disease may be associated with manifestations that escape an with the enzymatic defect and lysosomal storage of The understanding of the of GBA1 mutations and of glucosylceramide accumulation in macrophages and its on other cell severe has been described in some patients with Type 1 Gaucher disease, and this has its non-neuronopathic in Type 1 is believed to from within by gain of function mutations in GBA1 that lead to N370S is such a or accumulation of rare but fatal of Type 1 is pulmonary hypertension that occurs in and may of cells in the disease Other of complications peripheral and hematologic malignancies [9, The increased risk of multiple myeloma and in Type 1 Gaucher disease has been to chronic immune macrophages Type 3 Gaucher disease a distinct is associated with homozygosity for mutation that disease, and and [40. is the most severe of Type 2 disease, a that is in GBA1 these have the of Gaucher disease. into the of Gaucher disease have revealed important of cell other than in of Gaucher disease the the management of Gaucher disease and the for affected patients has a and it an of to the in the of phenotypic of Gaucher disease, the and understanding of the of enzyme replacement therapy with imiglucerase into algorithms for management. Further is with in gene therapy and therapy for mutations that result in defects A is therapy that to to therapy for with 22, this is likely to represent a significant to current therapy and to some of the in of diagnosis using blood will access to testing and timely diagnosis. The to develop diagnostic and disease management algorithms was in of the for and early diagnosis of Gaucher disease among hematologists [8. Genzyme an to the consensus of in and the management of Gaucher disease convened in to and clinical with the of developing diagnosis and management algorithms for Gaucher disease. out of by or of by on such as to individual to also by to from the Gaucher Registry of patients world The 10 experience of Gaucher disease presentations and in of the world in an to of the a of the of misdiagnosis from case are included in Appendix). the first meeting of of misdiagnoses in Gaucher disease, presenting sign and symptoms in Gaucher patients from clinical and those described in the on these key diagnostic These the for the of diagnostic The algorithms for diagnosis and management of Gaucher disease developed and and between The authors are to for with of the or in this are those of the from and had to a body for several Further not performed at this the age of was diagnosed with Gaucher disease for N370S family screening a diagnosis of Gaucher disease in The patient had mild splenomegaly, and was not the patient was that had mild Type 1 Gaucher disease and not the patient had an onset of severe bone in the (Fig. of liver volume × and spleen volume × avascular and of the of childhood MRI revealed avascular the and The patient had score of (normal range to the age of enzyme the age of replacement. (a and b). MRI showing avascular in the in a homozygous for N370S mutation with and cytopenia There is infarction in the that eventually replacement. There is of marrow in the due to marrow normal marrow MRI is depicted in that in childhood due to avascular was not When the patient was diagnosed with Gaucher disease as an adult family severe bone disease was not identified due to on and hematologic which indicated only mild disease. A was for chronic liver disease due to the finding of and elevated liver negative and The patient had chronic bone in diagnosed as the age of was diagnosed with of severe anemia and due to thrombocytopenia Bone marrow examination revealed almost replacement by Gaucher A diagnosis of Type 1 Gaucher disease was glucocerebrosidase revealed chronic liver disease and bone marrow The patient for with bone disease, liver disease, and eventually bone marrow a routine a Ashkenazi was found to have and hyperferritinemia was blood and was for an with early onset disease. A liver biopsy revealed Gaucher cells (Fig. The diagnosis of Type 1 Gaucher disease was by low acid β-glucosidase activity in blood leukocytes and homozygosity for the N370S Further revealed splenomegaly and biopsy showing accumulation of of cells Gaucher in the to normal A was diagnosed with Gaucher disease on liver biopsy performed for of and are common in Gaucher disease. A was followed for for severe thrombocytopenia, diagnosed as immune thrombocytopenia was with without The patient had a previous and developed pain, which was to be to the was to because of Further revealed splenomegaly, advanced avascular of the and Bone marrow biopsy revealed Gaucher Misdiagnosis as led to chronic corticosteroid therapy and eventually to avascular and A patient a with symptoms due to However, there was and bone marrow revealed Gaucher The diagnosis was by low acid β-glucosidase activity in blood Further splenomegaly, elevated chitotriosidase, normal and Gaucher disease may be associated with symptoms. In this with A and abdominal examination and appropriate have the of Gaucher disease liver and bone marrow biopsy. procedures a high risk of bleeding in this