To assess correlations of patient demographics, including enzyme replacement therapy (ERT) with bone histology, to facilitate decisions of whether and when to perform hip replacement surgery in patients with Gaucher disease.
We examined the histology of surgically removed femoral heads and categorized findings by the presence or extent of osteonecrosis, Gaucher cell (GC) infiltration, and bone regeneration qualifiers using a tripartite histology-based scoring system.
Twenty-two patients with 26 bone specimens were evaluated. Seventeen patients (77%) were splenectomized, 16 (73%) received ERT, and 12 (55%) had the putatively milder genotype (N370S/N370S), with the rest putatively at increased risk for skeletal disease (N370S/other). The 3 histology subscores were applicable to all specimens. Osteonecrotic bone was seen in 19 of 26 (73%); osteoarthritis was seen in all cartilage specimens. Gaucher cell infiltration was not correlated with demographics or disease severity. A trend was noted between reduced GC infiltration and ERT (ρ = 0.407), but regeneration qualifiers were not correlated with ERT or other features.
Histologic findings of GC infiltration and bone regeneration qualifiers did not correlate with demographics or with exposure to ERT. Most specimens unexpectedly showed good regenerative responses to osteonecrosis despite heavy GC infiltration.
"First of all, bone disease has always been considered part of the clinical spectrum of Gaucher disease and it has become clear that only partial improvement of bone disease can be achieved with ERT. It appears that in patients with a longstanding history of Gaucher disease, aggregates of Gaucher cells cannot be cleared, even when high doses of enzyme are supplied for many years (de Fost et al 2008; Lebel et al 2013). Post-mortem studies have shown persistent Gaucher cells despite ERT in other tissues as well (Hulkova et al 2009). "
[Show abstract][Hide abstract] ABSTRACT: Treatment options for a number of lysosomal storage disorders have rapidly expanded and currently include enzyme replacement therapy, substrate reduction, chaperone treatment, hematopoietic stem cell transplantation, and gene-therapy. Combination treatments are also explored. Most therapies are not curative but change the phenotypic expression of the disease. The effectiveness of treatment varies considerably between the different diseases, but also between sub-groups of patients with a specific lysosomal storage disorder. The heterogeneity of the patient populations complicates the prediction of benefits of therapy, specifically in patients with milder disease manifestations. In addition, there is a lack of data on the natural history of diseases and disease phenotypes. Initial trial data show benefits on relevant short-term endpoints, but the real world situation may reveal different outcomes. Collaborative international studies are much needed to study the long-term clinical efficacy of treatments, and to detect new complications or associated conditions of the diseases. This review summarizes the available treatment modalities for lysosomal storage disorders and the challenges associated with long term clinical care for these patients.
[Show abstract][Hide abstract] ABSTRACT: Gaucher disease is an inborn error of metabolism due to a deficiency of the lysosomal enzyme glucocerebrosidase. As a result of this deficiency, the substrate glucocerebroside accumulates in the liver, spleen, bone and bone marrow. Bone involvement can lead to abnormalities in bone growth, bone remodeling, bone infarcts, aseptic necrosis, osteonecrosis, increased fracture risk and lytic bone lesions. Patients may experience bone pain and bone crises related to bone infarcts. There is evidence of abnormal bone metabolism in both bone resorption and bone formation based upon biochemical abnormalities found in patients. In addition, both immunological and coagulation abnormalities have in part been implicated in the causation of bone disease. Treatment with enzyme replacement therapy and substrate reduction therapy has led to improvement in both the symptoms and the radiographic abnormalities seen in these patients. It is unknown whether these treatments lower fracture risk.
Expert Review of Endocrinology & Metabolism 02/2014; 9(2). DOI:10.1586/17446651.2014.887434
[Show abstract][Hide abstract] ABSTRACT: Gaucher disease (GD) is a lysosomal storage disorder characterized by accumulation of glucosylceramide in macrophages, so-called Gaucher cells, as a result of a deficiency of the lysosomal enzyme glucocerebrosidase. Bone complications are an important cause of morbidity of GD and are thought to result from imbalance in bone remodeling. Bone manifestations among GD patients demonstrate a large variation including increased osteoclastic bone resorption, low bone formation and osteonecrosis. The purpose of the current case series is to describe the histological features observed in undecalcified bone samples, obtained from three GD patients, and evaluate the relationship with clinical features in these patients. Bone fragments were obtained from three adult type 1 GD patients with variable degrees of bone disease during orthopedic surgery. Specimens were embedded without prior decalcification in methylmethacrylate and prepared for histology according to standardized laboratory procedures. Histology revealed a heterogeneous pattern of bone involvement. High cellularity of bone marrow, abundant presence of Gaucher cells (GCs) and high turnover were observed in a patient with a history of multiple bone complications, while minimal bone turnover and few GCs were detected in the mildest affected patient in this series. An intermediate picture with relatively low bone turnover and a substantial amount of Gaucher cells was demonstrated in the third, moderately affected patient. No gross abnormalities in three biochemical markers of bone turnover (osteocalcin, N-terminal propeptide of type 1 procollagen and type 1 collagen C-terminal telopeptide) were noted. Plastic embedding and subsequent Goldner and TRAP staining offered a unique possibility to study bone histological findings in GD. Our data show that bone manifestations in GD may vary both clinically as well as histologically and bone disease in GD will likely require a personalized approach.
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