Energy balance, glucose and lipid metabolism, cardiovascular risk and liver disease burden in adult patients with type 1 Gaucher disease

Nascimbeni, Fabio; Salda, Annalisa Dalla; Carubbi, Francesca

doi:10.1016/j.bcmd.2016.10.012

Cited by 31 publications

(32 citation statements)

References 56 publications

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“…ERT has been associated with weight gain [26–28] and increases in fat mass and body mass index due to metabolic changes, such as decreased resting energy expenditure and basal metabolic rate [27, 35], perhaps resulting from improved disease state. These are risk factors for developing diabetes, although direct correlation with ERT is unclear [36]. Although weight gain is not necessarily undesirable, the observed weight gain with ERT has been larger than would be expected purely as result of treatment for a disease in which pre-treatment resting energy expenditure is elevated.…”

Section: Discussionmentioning

confidence: 99%

Long-term adverse event profile from four completed trials of oral eliglustat in adults with Gaucher disease type 1

Peterschmitt

Freisens

Underhill

et al. 2019

Orphanet J Rare Dis

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Background Eliglustat is a first-line oral treatment for adults with Gaucher disease type 1 who have an extensive, intermediate or poor CYP2D6 metabolizer phenotype (> 90% of patients). Whereas enzyme replacement therapy for Gaucher disease has been widely used for more than two decades, eliglustat has only been in commercial use since 2014. Clinicians and patients want to better understand which adverse events are most commonly associated with eliglustat, as well as their severity, frequency, and duration. Methods This pooled analysis of treatment-emergent adverse events combines data from four completed eliglustat clinical trials involving 393 Gaucher disease type 1 patients. It represents 1400 patient-years of eliglustat exposure and a mean treatment duration of 3.6 years (maximum: 9.3 years). Results Eighty-one percent of patients remained in their respective trial until commercial availability of eliglustat (US patients only) or until trial completion. Nine patients (2.3%) withdrew from their respective trial due to one or more adverse events reported as eliglustat treatment-related; all but one of these events were mild or moderate. Overall, 97% of adverse events were mild or moderate and 86% were reported by the investigator as unrelated to eliglustat treatment. The overall rate of adverse events decreased over time and did not increase with increasing eliglustat dose. We evaluated frequency, duration, and severity of 14 adverse event terms reported at least once as treatment-related in 2% or more of all patients: dyspepsia (5.9%), headache (5.3%), abdominal pain upper (5.1%), dizziness (5.1%), diarrhea (4.6%), nausea (4.6%), arthralgia (3.6%), constipation (3.3%), abdominal pain (2.8%), gastroesophageal reflux disease (2.8%), fatigue (2.8%), palpitations (2.8%), abdominal distension (2.5%), and gastritis (2.3%). For abdominal pain upper, diarrhea, nausea, abdominal pain, and headache events, median duration was less than 14 days. All 14 adverse event terms, except for arthralgia and headache, were reported only once per patient in more than 70% of patients experiencing the event. Conclusions This final pooled analysis of treatment-emergent adverse events reinforces the favorable safety profile of eliglustat. The majority of the most frequently reported treatment-related adverse events were mild or moderate, transient, and occurred only once per patient. Electronic supplementary material The online version of this article (10.1186/s13023-019-1085-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Long-term adverse event profile from four completed trials of oral eliglustat in adults with Gaucher disease type 1

Peterschmitt

Freisens

Underhill

et al. 2019

Orphanet J Rare Dis

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“…Nonetheless, because of phenotypic heterogeneity and lack of awareness, other “high‐risk patterns” need to be considered. Biochemical abnormalities commonly found in GD include hyperferritinemia, hypolipidemia with low HDL‐cholesterol levels, low vitamin B12, polyclonal hypergammaglobulinemia, and MGUS …”

Section: Discussionmentioning

confidence: 99%

“…Regarding hyperferritinemia, it was initially attributed to metabolic syndrome, and improvement of lifestyle was recommended. Of note, obesity is uncommon in untreated GD patients . Although liver biopsy and normal TSat substantially excluded a true iron overload (IO), the patient was initially treated by unnecessary phlebotomies.…”

Section: Case Presentationmentioning

confidence: 99%

Hyperferritinemia and diagnosis of type 1 Gaucher disease

et al. 2020

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A 61-year-old Caucasian man presented with persistent hyperferritinemia known since his forties in the presence of components of metabolic syndrome. History revealed longstanding obesity, with maximum weight and BMI of 100 kg and 32 kg/m 2 , respectively. At the age of 45 years, routine blood examination showed marked hyperferritinemia (1738 μg/L) with normal transferrin saturation (TSat 41%), very mild thrombocytopenia (140 × 10 9 /L), normal Hb (139 g/L) and white blood cell count (8.93 × 10 9 /L), and polyclonal hypergammaglobulinemia (21.5%). He also had low HDL cholesterol (0.8 mmol/L), mild hypertriglyceridemia (2.33 mmol/L), impaired fasting glucose (5.66 mmol/L), and oral glucose tolerance test (OGTT) consistent with glucose intolerance (glucose 9.49 mmol/L at 2 hours). Liver function tests were normal, as well as C-reactive protein, coagulation, renal and thyroid function tests. At that time, he reported an unbalanced diet with moderate alcohol consumption, sedentariness, and positive family history for type 2 diabetes mellitus. Abdominal ultrasonography (US) showed mild liver enlargement with increased echogenicity consistent with moderate steatosis; the major diameter of the spleen was 12.4 cm; no signs of portal hypertension were detected. Liver biopsy demonstrated micro-macrovesicular steatosis in 50% of hepatocytes, and hypertrophic Kupffer cells with mild siderosis (Figure 1). A first-level genetic test for HFE-hemochromatosis was negative, only showing heterozygosity for the H63D variant. Sequencing of the SLC40A1 gene (encoding ferroportin) did not reveal pathogenic mutations. A provisional diagnosis of dysmetabolic iron overload syndrome (DIOS) was suggested, and lifestyle changes as well as alcohol withdrawal were recommended.Initially, Gaucher disease (GD) was not suspected. The patient had ≥2 alterations of the metabolic syndrome, liver steatosis and normal TSat, fitting the criteria for the diagnosis of DIOS, 1 which represents a far more frequent cause of hyperferritinemia than GD. A possible Ferroportin Disease, suggested by iron accumulation in Kupffer cells, 2 was ruled out by SLC40A1 sequencing.In the following 15 years, the patient lost weight (8 kg, leading to BMI reduction to 28 kg/m 2 ), and substantially improved his metabolic profile (fasting glucose 4.88 mmol/L, OGTT normalization, HDL cholesterol 1.39 mmol/L, triglycerides 0.93 mmol/L); he also underwent irregular phlebotomies (total n = 12). Nonetheless, serum ferritin was only mildly reduced (1056 μg/L). Of note, hypergammaglobulinemia (21%) was confirmed, and platelet count further decreased § Alberto Piperno and Domenico Girelli equally contributed to the work.

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“…Health status and comorbidities associated with GD, including obesity, malignancies, diabetes, gallstones and Parkinson’s disease, were examined in this study 3 16 28 33 34. Data suggest that the role of lysosomes in metabolic pathways, which affect energy balance, glucose and lipid metabolism, cardiovascular risk and liver disease, may result in an increased risk of weight gain, insulin resistance, cardiovascular disease and hepatocellular carcinoma among patients with lysosomal disorders 34–38. Our findings of higher rates of overweight and obesity among patients with GD compared with the general population, for example, support these lysosome-related mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Population-based cohort of 500 patients with Gaucher disease in Israel

Jaffe¹,

Flaks‐Manov

Benis

et al. 2019

BMJ Open

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ObjectiveTo characterise a population-based cohort of patients with Gaucher disease (GD) in Israel relative to the general population and describe sociodemographic and clinical differences by disease severity (ie, enzyme replacement therapy [ERT] use).DesignA cross-sectional study was conducted.SettingData from the Clalit Health Services electronic health record (EHR) database were used.ParticipantsThe study population included all patients in the Clalit EHR database identified as having GD as of 30 June 2014.ResultsA total of 500 patients with GD were identified and assessed. The majority were ≥18 years of age (90.6%), female (54.0%), Jewish (93.6%) and 34.8% had high socioeconomic status, compared with 19.0% in the general Clalit population. Over half of patients with GD with available data (51.0%) were overweight/obese and 63.5% had a Charlson Comorbidity Index ≥1, compared with 46.6% and 30.4%, respectively, in the general Clalit population. The majority of patients with GD had a history of anaemia (69.6%) or thrombocytopaenia (62.0%), 40.4% had a history of bone events and 22.2% had a history of cancer. Overall, 41.2% had received ERT.ConclusionsEstablishing a population-based cohort of patients with GD is essential to understanding disease progression and management. In this study, we highlight the need for physicians to monitor patients with GD regardless of their ERT status.

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Energy balance, glucose and lipid metabolism, cardiovascular risk and liver disease burden in adult patients with type 1 Gaucher disease

Cited by 31 publications

References 56 publications

Long-term adverse event profile from four completed trials of oral eliglustat in adults with Gaucher disease type 1

Long-term adverse event profile from four completed trials of oral eliglustat in adults with Gaucher disease type 1

Hyperferritinemia and diagnosis of type 1 Gaucher disease

Population-based cohort of 500 patients with Gaucher disease in Israel

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