Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019214 (hepatosplenomegaly)
 4,408 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modified placental human glucocerebrosidase (alglucerase) and recombinant glucocerebrosidase (imiglucerase) are effective means of treating Type 1 Gaucher's disease. Amelioration of hepatosplenomegaly and of haematological manifestations is usually apparent within 6 months. Bone disease responds more slowly but within several years improvement is evident in most patients. Analysis of a large body of data demonstrates that the rate of response of all manifestations of Gaucher's disease is independent of dose over the range of 30 to 260 U/kg body weight per month. Even the response to 15 U/kg per month appears to be equivalent under most circumstances; treatment failures are the same in patients treated with 15, 30 and 130 U/kg per month. Patients with severe manifestations respond more rapidly than those with mild disease, and this, too, is true at all but the 15 U/kg per month dosage level. All available data thus support the administration of no more than 15 to 30 U of alglucerase or imiglucerase per kg/month. Frequent dosing, i.e. three times weekly, appears to be the most effective means of administration.
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PMID:Enzyme replacement therapy for Gaucher's disease. 949 62

Gaucher disease is caused by a deficiency of glucocerebrosidase, resulting in hepatosplenomegaly, pancytopenia, growth retardation and skeletal involvement. We analyzed data on genotype and key clinical parameters in 35 Japanese patients with Gaucher disease type 1. Our data demonstrated that over 60% of patients had onset of Gaucher disease signs/symptoms at less than 5 years. Sixty percent and 46% of evaluable patients were splenectomized and developed severe bone involvement, respectively. Within mean follow-up periods of 8 years and 4 months, mean relative height and weight, severity score index and platelet count all worsened to a highly significant degree. These data suggest that type 1 Gaucher disease tends to be severe and progressive in Japanese patients, most of whom would be suitable for treatment and might indeed require earlier and more aggressive therapy.
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PMID:Type 1 Gaucher disease: phenotypic expression and natural history in Japanese patients. 954 79

Gaucher's disease is an autosomal recessive lysosomal storage disease, resulting from a deficiency of the enzyme glucocerebrosidase, which is required for the lysosomal degradation of glycolipids. The clinical manifestations of the disease show a large heterogeneity, including hepatosplenomegaly, "bone crisis" and fracture, anemia, thrombocytopenia and, in the rarest types II and III, neurological decompensation. Type I, the most common form, usually presents with less severe symptoms and at a more advanced age. More than 30 mutations within the glucocerebrosidase gene have been recognized, and certain mutations seem to be related with a particular phenotype expression of the disease. Modern diagnosis of Gaucher's disease is performed by either determining the enzyme activity in peripheral blood leukocytes or through DNA-based analysis. Pregnancy concurrent with Gaucher's disease has several risks, including an increased severity of anemia and thrombocytopenia that can potentiate postpartum bleeding, and increased risk of infection and possibly an increased spontaneous abortion rate. Nevertheless, the majority of these pregnancies seem to proceed to term without significant complications. The effects that pregnancy might have on the course of the disease are still unresolved. Enzyme replacement therapy with alglucerase is the treatment of choice for patients with Gaucher's disease, but it is yet to be shown whether alglucerase reduces the risk of these complications during pregnancy and whether its use has any adverse effect on fetal development. We present an extensive review of the current literature regarding Gaucher's disease with special emphasis on pregnancies coexistent with this disease and, an analysis of the genetics, relevant prenatal diagnostic issues, and current treatment modalities.
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PMID:Gaucher's disease and pregnancy. 964 38

We report the case of a 46-year-old female with coexisting type I Gaucher's disease and chronic myeloid leukemia (CML). The diagnosis of Gaucher's disease was made in early childhood by bone marrow biopsy and was recently confirmed by biochemical demonstration of reduced leukocyte beta-glucocerebrosidase activity and the presence of Gaucher cells in a bone marrow aspirate. We analyzed the patient's genomic DNA for the underlying glucocerebrosidase mutations and have found homozygosity for a C-->T transition in cDNA nucleotide 593 (159 Pro-->Leu), presently an undescribed mutation. After initiation of replacement therapy with alglucerase we observed a significant increase of the platelet count in our patient. The diagnosis of CML was based on standard hematological parameters and the detection of the Philadelphia chromosome (Ph). With intermittent treatment with busulfan the patient has remained in chronic phase for nine years. The patient suffered from hepatosplenomegaly and thrombocytopenia, both of which can be caused by Gaucher's disease and CML. The aggravation of skeletal manifestations of Gaucher's disease, which occurred at the time of diagnosis of CML, could be due to increased production of leukocyte-derived glucocerebrosides that were not appropriately degraded because of the genetic beta-glucocerebrosidase deficiency.
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PMID:Coincidence of Gaucher's disease due to a private mutation and Ph' positive chronic myeloid leukemia. 972 84

Alglucerase is a modified form of human placental glucocerebrosidase used as enzyme replacement therapy for patients with Gaucher's disease, in whom functional glucocerebrosidase is deficient. Alglucerase has provided a breakthrough in treatment for patients with this relatively rare disease. With alglucerase infusions typical disease manifestations are ameliorated or normalised: hepatosplenomegaly is reduced, haematological parameters improve, and patients experience an increased quality of life usually within 4 to 6 months of treatment. Parameters of bone disease also respond, but generally over a longer period of treatment. Alglucerase is well tolerated by children and adults, with few adverse effects reported. Seroconversion occurs in approximately 15% of patients on high-dose therapy, but does not appear to affect the efficacy of treatment. Several dosage regimens have been used to deliver alglucerase, and the comparative benefits of these remain controversial. High-dose regimens of 60 IU/kg bodyweight administered every 2 weeks are clearly effective; however, smaller dosages given more frequently are also effective and incur a greatly reduced acquisition cost. Patient responses are variable, and the dosage regimen should be tailored to individual needs. Dosage regimens may be considerably reduced for the maintenance phase of treatment, but clinical experience is as yet insufficient to establish the minimum dosages required in the long term. Acquisition cost of alglucerase is $US3.70 per unit (1994 US dollars); thus, a dosage regimen of 60 IU/kg bodyweight administered every 2 weeks for a patient weighing 70kg costs $US404,040 per year. The minimal costs per quality-adjusted life year saved (QALY) have been estimated for 3 dosage regimens over a 10-year period. Cost per QALY was $US147,000 for 60 IU/kg bodyweight administered every 2 weeks, $US75,000 for 30 IU/kg every 2 weeks, and $US49,000 for 2.3 IU/kg administered 3 times per week. These costs were calculated assuming immediate death with no treatment, which suggests that the actual costs per QALY for most patients with type 1 or 3 disease are likely to be much higher. Drug administration costs may become a significant part of the cost during maintenance therapy; in addition, possible cost savings due to increased patient productivity and reduced palliative treatments remain unresolved. Although some patients may obtain increased benefit from high-dosage regimens, the very high cost may preclude general use of these regimens. Healthcare resources consumed by alglucerase therapy represent a large opportunity cost for other therapeutic areas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alglucerase. A pharmacoeconomic appraisal of its use in the treatment of Gaucher's disease. 1015 4

Imiglucerase, the recombinantly produced enzyme, is gradually replacing the human placental derived alglucerase in the treatment of gaucher patients. We describe the first case, to the best of our knowledge, of an anaphylactoid reaction to imiglucerase in a patient who tolerated alglucerase. The patient was diagnosed at the age of 2 4/12 years with anemia and hepatosplenomegaly. Over the years he had suffered from marked splenomegaly, thrombocytopenia and recurrent bleeding episodes. At the age of 24 he started treatment with imiglucerase. After 3 months of treatment, immediately after starting an infusion, he experienced flushing, cough, tachycardia, palpitation, chest pain and excessive sweating, which reoccurred on a consecutive administration. Substitution with alglucerase was tolerated well, with only mild rash when he was premedicated with benadryl. Immediate skin tests to alglucerase, imiglucerase and gelatin were negative. IgG against alglucerase was undetectable. The in vitro mast cell degranulation test was positive for alglucerase, imiglucerase heamaccel (a gelatin based plasma substitute, which is a component of imiglucerase). This sensitivity to imiglucerase but not to alglucerase, raises the question of future treatment for this patient, since the production of alglucerase may cease, once imiglucerase production will cover the need for replacement enzyme.
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PMID:Anaphylactoid reaction to imiglucerase, but not to alglucerase, in a type I Gaucher patient. 1038 90

A 36-year-old woman was admitted for hepatosplenomegaly and anemia. Bone marrow cytology showed "sea-blue histiocytes", vacuolated macrophages and plasma cells. As primary liver disease, malignancy or hematologic disorders were excluded, and plasma chitotriosidase activity was increased 27-fold over control, the presence of a lysosomal storage disease was suspected. Biochemical analysis of skin fibroblasts revealed normal glucocerebrosidase and sphingomyelinase activity, but lipid analysis showed a more than 15-fold accumulation of cholesterol esters within the cells. The activity of lysosomal acid lipase (LAL) in fibroblast homogenates was decreased to 12% of control subjects. Mutational analysis of the patient's blood showed the homozygous G-->A mutation at position -1 of the exon 8 splice donor site (E8SJM-allele) known for adult cholesteryl ester storage disease (CESD); the polymorphic background was that of the complex haplotype -6Thr, 2Gly, 894 G-->A. Based on clinical, laboratory, cytological and and biochemical findings, CESD can clearly be separated from other more frequent inherited lysosomal storage diseases, e.g. atypical forms of Gaucher disease.
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PMID:Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase -1 exon 8 splice junction mutation. 1055

Gaucher disease is caused by an autosomal-recessive deficiency of glucocerebrosidase. Cells of monocytic/macrophagic origin accumulate glucosylceramide. This leads to hepatosplenomegaly, bone destruction, thrombocytopenia and anemia. Enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase leads to normalization of these parameters. The way of macrophage activation in Gaucher disease is not known. Recently, the osmolytes taurine, betaine and inositol were identified as important regulators of macrophage function in liver. Therefore, the role of plasma taurine in Gaucher disease as a primarily macrophage-derived disease was studied. Fasting plasma levels were measured from blood samples of healthy control subjects (n = 29, m:f = 11:18, mean age 37 +/- 3 years), from untreated Gaucher patients (n = 16, m:f = 7:9, mean age 44 +/- 4 years) and those treated for 37 +/- 2 months (n = 54, m:f = 19:35, mean age 47 +/- 2 years). Amino acid analysis was carried out in a BioChrom amino acid analyzer. In the untreated patients, plasma taurine was 45 +/- 3 microM, as compared to the controls with a plasma taurine of 63 +/- 4 microM (p < 0.01). The average increase of plasma taurine during the first year of ERT was 18 +/- 8 microM (n = 10). Patients treated for an average of 37 months (range 1-9 years of ERT) had a plasma taurine of 65 +/- 4 microM (n = 54), which was not different from the controls. It is concluded that Gaucher patients show decreased plasma taurine levels and that therapy of Gaucher disease might correct this. It has to be established, whether decreased taurine availability is a cofactor of the permanent activation of glucosylceramide-storing monocytes/macrophages in this disease.
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PMID:Decrease of plasma taurine in Gaucher disease and its sustained correction during enzyme replacement therapy. 1114 Mar 61

Gaucher disease is a genetic lipid storage disease and represents a potentially serious health problem. It arises from a deficiency of glucocerebrosidase activity with secondary accumulation of large quantities of glucocerebroside. Symptoms are usually multisystemic, often debilitating or disabling, and sometimes disfiguring, and they can lead to death. We report objective clinical response's to repeated infusion of human placental and recombinant glucocerebrosidase in 2 patients with type 1 Gaucher disease and increased hemoglobin levels and platelet counts. Splenic volume decreased during the period of enzyme administration. Enzyme replacement therapy has improved the treatment of type 1 Gaucher disease by safely and effectively arresting, decreasing, or normalizing many of its major signs and symptoms. Consideration by physicians must be given to Gaucher disease, and appropriate treatments must be given when confronted with cryptogenic pancytopenia or hepatosplenomegaly.
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PMID:Improvement of splenomegaly and pancytopenia by enzyme replacement therapy against type 1 Gaucher disease: a report of sibling cases. 1134 3

A 27-year-old woman was admitted for further examination of thrombocytopenia. Symptoms were absent, but physical examination demonstrated hepatosplenomegaly without neurological abnormalities. Bone marrow examination revealed many Gaucher cells, and glucocerebrosidase activity from cultured skin fibroblasts was markedly reduced. A 1448C (L444P) mutation was detected on one allele of the glucocerebrosidase gene. Because magnetic resonance imaging (MRI) of the femora indicated severe infiltration of Gaucher cells into bone marrow, enzyme replacement therapy was initiated despite the absence of skeletal symptoms. Hematologic abnormalities, visceral and bone involvement have been improving. In cases of thrombocytopenia or hepatosplenomegaly, Gaucher's disease should be suspected.
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PMID:Initiation of enzyme replacement therapy for an adult patient with asymptomatic type 1 Gaucher's disease. 1151 9


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