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Background & aims Long-term liver-related complications of Gaucher disease (GD) include cirrhosis, portal hypertension and hepatocellular carcinoma. Although liver fibrosis is the main determinant of adverse liver-related clinical outcomes, it has rarely been evaluated in previously published cohorts of GD patients. We aimed at: assessing the prevalence of significant liver fibrosis in a cohort of patients with type 1 GD; identifying its predictors among GD-related variables, enzyme replacement therapy (ERT) and metabolic features. Methods 37 adult type 1 GD patients from two Italian academic referral centers were prospectively submitted to vibration controlled transient elastography (Fibroscan®); significant fibrosis was defined as liver stiffness ≥7 kPa. Results Median liver stiffness was 4.6 [3–15.1] kPa and 7 patients (19%) had significant fibrosis. Significant fibrosis was associated with splenectomy (p = .046) and with scores (DS3: p = .002; SSI: p = .026) and biomarkers (ACE: p = .016; HDL cholesterol: p = .004) of GD severity. Length of ERT was significantly lower in GD patients with significant fibrosis. In the subgroup of 29 patients who were on stable ERT for at least 24 months, further to splenectomy, GD severity and non-N370S GBA1 genotypes, also diastolic blood pressure, BMI and the number of metabolic syndrome (MetS) components emerged as factors significantly associated with significant fibrosis. Conclusions Significant fibrosis is present in a remarkable proportion of adult type 1 GD patients. Splenectomy, GD severity and GBA1 genotypes are major GD-related predictors of liver fibrosis. Length of ERT is inversely correlated with liver disease in GD patients, suggesting a beneficial effect of ERT on liver fibrosis. However, GD patients on stable ERT should be monitored for metabolic complications, since MetS features may enhance liver disease progression despite optimal GD control.

Gaucher disease is characterized by multi-organ infiltration of phospholipid-laden macrophages. Bone involvement is characterized by typical deformities, osteopenia/osteoporosis, pathological fractures, and bone marrow infiltration (avascular osteonecrosis, infarction). Estimation of skeletal disease includes bone quality that contributes substantially to bone strength. We studied 23 type 1 Gaucher patients (median age 22years, range 3-73) on Enzyme Replacement Therapy from 2months to 26years (median 7years); 4 patients had pathological fractures, 10 bone infarctions, 6 avascular osteonecrosis. We noninvasively assessed bone quality by trabecular microarchitecture and macroscopic geometry, using two innovative dual-energy X-ray absorptiometry tools: Trabecular Bone Score (TBS) and Hip Structural Analysis (HSA). Bone quality parameters distinguished the patients with skeletal complications. TBS was significantly lower in patients with avascular osteonecrosis (p=0.049) and pathological fractures (p=0.024), while it could not identify those with bone infarctions. Among HSA parameters, the Cross Sectional Area of the intertrochanteric region and the Buckling Ratio of the narrow neck allowed the distinction of patients with avascular osteonecrosis. BMD was low in 11 patients (50%); neither BMD nor HSA were associated with pathological fractures. The combined evaluation of bone quality and bone quantity is useful to identify GD patients with more severe skeletal involvement.

The availability of three iron chelators improved the scenario of chelation therapy for transfusion-dependent thalassemia (TDT) patients, allowing tailoring of drugs according to the goals expected for each patient. The use of Deferiprone/Deferoxamine (DFP/DFO) combined in different schemes has been reported since many years. Only recently data from combination of Deferasirox/Deferoxamine (DFX/DFO) have been reported showing that it can be safe and efficacious to remove iron overload, particularly in patients who do not respond adequately to a single chelating agent. We investigated the efficacy, tolerability and safety of combined DFX/DFO in thalassemia major patients. Ten TDT patients have started DFX/DFO for different reasons: 1) lack of efficacy in removing liver/cardiac iron with monotherapy; 2) agranulocytosis on DFP; and 3) adverse events with elevated doses of monotherapies. The study design included: cardiac and hepatic T2* magnetic resonance (CMR), transient elastography evaluation (Fibroscan), biochemical evaluation, and audiometric and ocular examinations. The drugs' starting doses were: DFO 32 ± 4 mg/kg/day for 3-4 days a week and DFX 20 ± 2 mg/kg/day. Seven patients completed the one-year follow-up period. At baseline the mean pre-transfusional Hb level was 9.4 ± 0.4 g/dl, the mean iron intake was 0.40 ± 0.10mg/kg/day, the median ferritin level was 2254 ng/ml (range 644-17,681 ng/ml). Data available at 1 year showed no alteration of renal/hepatic function and no adverse events. A marked reduction in LIC (6.54 vs 11.44 mg/g dw at baseline) and in median ferritin (1346 vs 2254 ng/ml at baseline) was achieved. A concomitant reduction of non-transferrin-bound iron (NTBI) at six months was observed (2.1 ± 1.0 vs 1.7 ± 1.2 μM). An improvement in cardiac T2* values was detected (26.34 ± 15.85 vs 19.85 ± 12.06 at baseline). At 1 year an increased dose of DFX was administered (27 ± 6 mg/kg/day vs 20 ± 2 mg/kg/day at baseline, p=0.01) with a stable dose of DFO (32 ± 4 mg/kg/day). Combined or alternated DFX/DFO can be considered when monotherapy is not able to remove the iron overload or in the presence of adverse events.

To determine the prevalence and spectrum of ocular fundus abnormalities in patients with β-thalassemia and to investigate risk factors for their development.Cross-sectional, observational study.A total of 255 patients with β-thalassemia major (TM) and β-thalassemia intermedia (TI) were consecutively recruited and investigated.Patients underwent best correct visual acuity, indirect ophthalmoscopy, and fundus photography, including fundus autofluorescence (FAF) and near-infrared reflectance imaging using a confocal scanning laser ophthalmoscope (cSLO). Hematologic parameters were determined, including mean ferritin levels, aspartate amino transferase, alanine amino transferase, calcium, pre-transfusion hemoglobin, history of splenectomy, and liver iron concentration. Factors associated with the ocular phenotype were assessed using logistic regression.Ocular phenotype as determined by clinical examination and used multimodal imaging.A total of 153 patients (60.0%) affected by TM and 102 patients (40.0%) affected by TI participated, of whom 216 (84.7%) were receiving iron-chelating therapy. Ocular fundus abnormalities characteristic of pseudoxanthoma elasticum (PXE) were detected by cSLO in 70 of 255 patients (27.8%) and included peau d'orange (19.6%), angioid streaks (12.9%), pattern dystrophy-like changes (7.5%), and optic disc drusen (2.0%). Pseudoxanthoma elasticum-like changes were more frequent in patients with TI (P0.001). Patients with PXE-like fundus changes were older than patients without these fundus changes (P0.001). In both patients with TI and TM, age (P = 0.001) and splenectomy (P = 0.001) had the strongest association with presence of PXE-like fundus changes in multivariate analyses. A total of 43 of 255 patients (16.9%) showed increased retinal vascular tortuosity independently of the PXE-like fundus changes, which was associated with aspartate amino transferase (P = 0.036), hemoglobin (P = 0.008), and ferritin levels (P = 0.005).Pseudoxanthoma elasticum-like fundus changes are a frequent finding in patients with β-thalassemia. In TI, these changes increase with duration or severity of the disease. This particular ocular phenotype suggests an ocular pathology similar to PXE. Retinal vascular tortuosity may be an additional disease manifestation independent of the PXE-like syndrome. Patients with long-standing disease requiring iron-chelating treatment and a history of splenectomy need regular ophthalmic checkups because they are at risk of developing PXE-like fundus changes and potentially of subsequent choroidal neovascularization.

Gaucher disease (GD), the most common inherited lysosomal storage disorder, is a multiorgan disease due to an autosomal recessive defect of the gene encoding glucocerebrosidase enzyme, responsible for the accumulation of glucosylceramide (glucocerebroside) into reticuloendothelial cells, particularly in the liver, spleen and bone marrow. GD is a clinically heterogeneous disorder and it is conventionally classified in type 1 (non-neuronopathic disease), types 2 and 3 (acute and chronic neuronopathic disease, respectively). Features of clinical presentation and organ involvement as well as age, at presentation are highly variable among affected patients. Splenomegaly and/or thrombocytopenia are the most common presenting features either as incidental findings during routine blood count or physical examination. Other possible clinical manifestations can be hepatomegaly with abnormal liver function tests, bone pain often associated with skeletal complications (pathological fractures, avascular necrosis, osteopenia), pulmonary hypertension and, in neuronopathic forms, neurological manifestations (dysfunction of eye motility, mild mental retardation, behavioural difficulties, choreoathetosis and cramp attacks). For all these reasons GD diagnosis is often a real challenge for internists. In the presence of clinical suspicion of GD, the diagnosis has to be confirmed measuring the betaglucocerebrosidase activity in the peripheral leukocytes and by molecular analysis. Each patient needs an accurate initial multisystemic assessment, staging the damage of all the possible organs involved, and the burden of the disease, followed by regular followup. The correct and early diagnosis permits to treat patients properly, avoiding the complications of the disease.

Background: Women with thalassaemia major typically experience hypogonadotropic hypogonadism because of the toxic effects of iron overload on the anterior pituitary. Moreover, in affected women, serum anti-Mullerian hormone (AMH) and antral follicle count (AFC) are also shown to be reduced, suggesting that the peripheral excess of iron could also harm the ovarian reserve. To date, the detrimental effects of the disease on oocyte quality have not been investigated. Materials and methods: Women with thalassaemia major who underwent in vitro fertilization (IVF) cycles were retrospectively identified over a 9 years period. They were matched (with a 1:5 ratio) by study period and age to a control group of infertile women undergoing IVF. Embriological variables were compared between the two groups. The primary outcome was the rate of top quality embryos. Results: Twenty-one women with thalassaemia major (exposed group) and 105 controls (unexposed group) were ultimately included. Serum AMH was 0.6 [0.2–1.8] and 1.5 [0.7–3.5] ng/ml, respectively (p = 0.05). AFC was 4 (1–7.5) and 11 (5.5–16), respectively (p

Background and aim. Transient elastography (TE) is a new, non-invasive and reproducible technique that measures liver stiffness (LSM). It has been demonstrated to be a reliable tool for assessing hepatic fibrosis and cirrhosis in patients with chronic liver disease (CLD). However, its role in patients with b- thalassemia has not been extensively investigated. The aim of the present study was to assess LSM and its possible correlation with iron overload in HCV positive patients with b- thalassemia major and intermedia. Methods. During a six-month period (from January to June 2007) 46 consecutive adults patients with b- thalassemia afferring to a single Italian Thalassemia Care Center in Milan, Italy, were enrolled in the study. Twenty-nine patients (Group I: 7 M and 23 F; mean age 31±SD 7.1 yrs; mean BMI 23.4±SD 3 Kg/m2) had b- thalassemia major and 17 intermedia (Group II: 10 M and 7 F; mean age 43±SD12.4 yrs; BMI 22 ±SD 3 Kg/m2). Sixteen patients (55%) in group I and two (12%) in group II were HCV RNA positive. All patients were examined by TE (FibroScan®; Echosens, Paris, France) and only the examinations with at least 10 validated measurements and a success rate of at least 60% were considered adequate. According to a previous study in CLD patients the considered TE cut off to diagnosing different stages of hepatic fibrosis were: >7.9 kPa for F≥2; >10.3 for ≥F3 and >11.9 for F=4. Twelve patients (all in group I) also had undergone liver biopsy. Necroinflammation and fibrosis were scored by METAVIR classification; liver iron concentration (LIC, mg/gr of liver dry weight) was measured on fresh tissue cores by atomic absorption spectrometry. Twenty-five patients underwent liver iron determination by T2* Magnetic Resonance Imaging (MRI) assessment. Results. In patients who underwent liver biopsy, LSM increased proportionally to the METAVIR stage and a significant positive correlation was observed between LSM and fibrosis stage (r=0.57, p= 0.039). Patients in group I had significantly higher values of mean LSM values (10.6± SD 9.3 kPa) and serum ferritin (SF) (1367±SD 1169 ng/mL) than those in group II (6.0± SD 3.3 kPa and 716±SD 472 ng/mL, respectively) (p=2) or severe fibrosis (F>=3) did not differ significantly according to HCV viremic status. Conclusion TE is a reliable non invasive technique to stage liver fibrosis in patients with b- thalassemia major. In these patients with concomitant HCV infection a significant or severe fibrosis was observed in about one third of the cases. Apart from fibrosis also serum necroinflammatory activity, GGT levels and SF levels may influence LSM values. The reliability of liver iron overload by T2* MRI evaluation remains still to be validated.