Accelerated skeletal deterioration after splenectomy in Gaucher type 1 disease

Rose, J.D.R.; Ga, Grabowski; Barnett, SH; Desnick, R. J.

doi:10.2214/ajr.139.6.1202

Cited by 50 publications

(9 citation statements)

References 5 publications

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“…Evaluating the study by Fiore and colleagues, we can observe that the patients' mean age was the same as in our study and, concerning the analysed bone markers, urinary deoxypyridinoline was measured using the same method. On the other hand, more than 50% of the studied population had been previously splenectomized, a condition that may lead to a greater burden of glucocerebroside on bone (Rose et al 1982), and their mean lumbar bone mineral density was far lower than that of our subjects (−2.16 versus −0.81). These contradictory results may thus be the consequence of heterogeneity in the severity of patients' disease and differing gravity of bone involvement in the cases studied.…”

Section: Discussionmentioning

confidence: 67%

Gaucher disease and bone: Laboratory and skeletal mineral density variations during a long period of enzyme replacement therapy

Ciana

Addobbati²,

Tamaro³

et al. 2004

J of Inher Metab Disea

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The usefulness of bone turnover markers in Gaucher disease is still unclear and their utility in monitoring the effects of enzyme replacement therapy (ERT) on bone metabolism has not yet been investigated exhaustively. Skeletal involvement seems to improve slowly during ERT, but only a few studies evaluating bone mineral density (BMD) changes during a long follow-up period have been reported. The aim of this study was to assess the efficacy of ERT on bone involvement in a group of 12 type I Gaucher disease (GD I) patients by monitoring biochemical indices of bone resorption/formation and BMD measured by dual energy x-ray absorptiometry (DEXA). Serum (calcium, phosphorus, bone alkaline phosphatase isoenzyme, carboxyterminal propeptide of type I procollagen (PICP), carboxyterminal telopeptide of type I collagen (ICTP), osteocalcin, intact parathyroid hormone) and urinary (calcium, phosphorus, hydroxyproline and free deoxypyridinoline) markers of bone metabolism and lumbar BMD were measured at baseline, after 6 and 12 months, and then every year for a mean ERT follow-up period of 4.5 years (range 4.4-6 years). Twelve healthy adult subjects matched for age and sex were tested as negative controls. A significant decrease of PICP was detected in the patient group at baseline (mean value 100.52 ng/ml vs 142.45 ng/ml, p = 0.017), while ICTP was remarkably higher: mean value 3.93 ng/ml vs 2.72 ng/ml, p = 0.004 (two-sided Student's t-test). No changes in bone formation indices were observed during the follow-up period, while urinary calcium excretion increased significantly from 0.065 to 0.191 mg/mg creatinine (p = 0.0014) (repeated measures ANOVA). A significant BMD improvement was also detected after an average ERT period of 4.5 years: Z-score increased from -0.81 to -0.56 (p = 0.005) (two-sided Student's t-test). These data evidenced the ineffectiveness of the biochemical markers used in monitoring ERT efficacy in GD I skeletal involvement, whereas DEXA was demonstrated to be a reliable method with which to follow up BMD improvement.

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Section: Discussionmentioning

confidence: 67%

Gaucher disease and bone: Laboratory and skeletal mineral density variations during a long period of enzyme replacement therapy

Ciana

Addobbati²,

Tamaro³

et al. 2004

J of Inher Metab Disea

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“…Macrophage-targeted enzyme replacement therapy with imigucerase is safe and effective in reversing or preventing many manifestations of type 1 GD, including hepatosplenomegaly, marrow infiltration, cytopenias, bone crises and osteopenia [16]. ERT with imiglucerase has virtually eliminated the need for splenectomy, which has been associated with pulmonary hypertension, fatal sepsis, advanced liver disease, and rapid progression of bone disease [17][18][19][20][21][22]. However, ERT cannot reverse established avascular necrosis, advanced bone disease, or hepatic, splenic or marrow fibrosis, underscoring the importance of timely treatment before irreversible complications develop [23].…”

Section: Discussionmentioning

confidence: 99%

Consequences of diagnostic delays in type 1 Gaucher disease: The need for greater awareness among Hematologists–Oncologists and an opportunity for early diagnosis and intervention

et al. 2007

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Gaucher disease (GD) is a progressive macrophage lipidosis capable of causing disabling and life-threatening complications. Anecdotal experiences suggest that GD may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy (ERT) with imiglucerase. We conducted surveys of patients and Hematology-Oncology specialists to assess the frequency of diagnostic delays. Additionally, we report a series of patients who suffered diagnostic delays and as a result developed disabilities including potentially life-threatening manifestations of GD. Of 136 patients surveyed, the average time from first appearance of GD symptoms to final diagnosis was 48.7 ± 123.6 months. More than two-thirds were evaluated and managed by a Hematologist-Oncologist (Hem-Onc). A global survey of 406 Hem-Oncs found that only 20% considered GD in the differential diagnosis for all of its classic symptoms (cytopenia, hepatosplenomegaly, bone pain); the diagnosis considered most likely included leukemia, lymphoma, and multiple myeloma. To illustrate actual consequences of diagnostic delays, we describe 14 patients with GD who suffered from symptoms for up to 10 years before correct diagnosis. Diagnostic delays led to complications that are preventable or reversible with ERT (i.e., avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, liver pathology). Patients homozygous for N370S mutation in this series were vulnerable to diagnostic delays. In conclusion, prolonged diagnostic delays occur in GD and may result in severe disease manifestations. Our findings suggest that physician education will increase the likelihood of prompt detection of GD and improve its management with ERT with imiglucerase when indicated. Am. J. Hematol. 82:697-701, 2007. V

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“…Consequently, these data do not support the use of splenectomy as an adjunct to lowering the enzyme dose required. In addition, the morbidity associated with splenectomy (19)(20)(21)(22)(23), per se, and in Gaucher disease, in particular (24,25), would indicate that reduction of splenic size by enzyme augmentation would be preferable to the surgical approach for the hematologic management of Gaucher disease patients. Importantly, extensive hepatic fibrosis (case 2) and cirrhosis (case 4) were present in severely involved patients who had splenectomies early in life.…”

Section: Discussionmentioning

confidence: 99%

Enzyme Augmentation in Moderate to Life-Threatening Gaucher Disease

et al. 1992

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ABSTRACT. Gaucher disease type 1 (GD type 1) is the most prevalent lysosomal storage disease and has its highest frequency in the Ashkenazi Jewish population. Deficiency of the enzyme, acid 8-glucosidase, results in the deposition of glucocerebroside primarily in macrophages. The accumulation of such "Gaucher cells" leads to visceromegaly, hepatic and bone marrow dysfunction, hypersplenism, and bony disease. Eleven GD type 1 patients, ages 4-52 y, with moderate to life-threatening manifestations, received 6-12 mo of enzyme augmentation with a macrophage-targeted acid 8-glucosidase preparation.Within 6 mo, substantial increases in Hb levels (mean = +30%) and platelet counts (mean = +39%) were observed. Hepatic and splenic volumes decreased by -20% (range = 3-35%) and -35% (20-52%), respectively. Hematologic and hepatic volume improvements were similar in the splenectomized (n = 4) and nonsplenectomized (n = 7) patient groups. In this patient population, no major differences were observed in the hematologic and visceral improvements with enzyme doses of 30, 50, or 60 IU/kg administered every 2 wk. Normal levels of acid 8-glucosidase activity were present in hepatic autopsy samples from one patient 11 d after enzyme infusion. In comparison, exogenous activity was absent from brain and lung specimens of the same patient. High levels (-10-fold normal) were present in bone marrow samples from two patients obtained at 1 and 11 d after infusions. These studies demonstrate biochemical and clinical improvements by targeted enzyme augmentation in GD type 1, even in far advanced, life-threatening involvement. These and previous studies indicate that earlier intervention in patients with more mild signs may be warranted to obviate the need to rescue extraordinarily ill patients with GD type 1. (Pediatr Res 31': 496-502, 1992) not absence, of the enzyme acid P-glucosidase and results from numerous point mutations at that locus (3

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Accelerated skeletal deterioration after splenectomy in Gaucher type 1 disease

Cited by 50 publications

References 5 publications

Gaucher disease and bone: Laboratory and skeletal mineral density variations during a long period of enzyme replacement therapy

Gaucher disease and bone: Laboratory and skeletal mineral density variations during a long period of enzyme replacement therapy

Consequences of diagnostic delays in type 1 Gaucher disease: The need for greater awareness among Hematologists–Oncologists and an opportunity for early diagnosis and intervention

Enzyme Augmentation in Moderate to Life-Threatening Gaucher Disease

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