Background Gaucher disease (GD) is a rare inherited lysosomal storage disorder, characterized by glycosphingolipids accumulation in cells of the reticulo-endothelial system due to deficiency of the lysosomal enzyme acid beta-glucosidase. Hepato-splenomegaly, cytopenia and bone disease represent the main features of type 1 GD. GD patients present a peculiar metabolic profile characterized by increased energy expenditure, systemic inflammation, peripheral insulin resistance and hypolipidemia. Liver disease is frequent and variable, ranging from benign hepatomegaly to fibrosis or cirrhosis. Enzyme replacement therapy and substrate reduction therapy have proven to be very effective on visceral and bone disease and to improve patients’ morbidity and quality of life. Aging GD patients, as the general population, may develop lifestyle-related metabolic risk factors with a potential impact on morbidity and mortality. Description of the studies Limited data are available about body composition, metabolic features, liver disease and lifestyle in GD. This project was designed to characterize the metabolic profile and the liver disease burden in a cohort of adult type 1 GD patients and to evaluate their relationship with GD variables and lifestyle. Patients were evaluated at baseline and follow-up visits, collecting data about GD severity and therapy, anthropometric and metabolic parameters; lifestyle habits were evaluated by validated questionnaires; body composition was assessed by DEXA and liver disease by abdominal ultrasound, magnetic resonance and liver transient elastometry (Fibroscan®). Preliminary study - In a cohort of 37 adult type 1 GD patients, a notable proportion (19%) showed significant liver fibrosis, defined as liver stiffness > 7 kPa, which was associated with GD severity features and a short therapy duration. Among patients on stable ERT, liver fibrosis was also significantly associated with the metabolic syndrome components, suggesting a potential role of metabolic comorbidities in liver disease progression. Study 1 – Within a subgroup of 20 patients of the cohort, metabolic comorbidities were widely represented and liver steatosis, defined as CAP value ≥ 250 dB/min, was detected in 40% of them. Significant steatosis was associated with metabolic syndrome, but not with GD severity variables and therapy duration. Moreover, patients with liver steatosis showed a worse metabolic profile and higher liver stiffness than the counterpart without steatosis. Study 2 – Then, we aimed at evaluating metabolic and liver-related comorbidities in relation to lifestyle and body composition. Analysis of the dietary and physical activity questionnaires showed, respectively, a high prevalence of unbalanced diet and physical inactivity. Body composition evaluation showed an increased fat mass and decreased bone and lean mass. Unbalanced diet and sedentariness were positively associated with indices of adiposity and metabolic syndrome features, suggesting that unhealthy lifestyle had a potential role on metabolic and liver complications in GD patients on stable ERT. Study 3 – Finally, we aimed at evaluating changes in metabolic profile over time and at identifying predictors of liver-related outcome in a longitudinal follow-up study. Conclusions Cardiometabolic risk factors, liver steatosis and fibrosis are highly prevalent and seem to be mainly related to unhealthy lifestyle in our adult GD cohort on stable therapy. For that reason, a cardiometabolic and lifestyle assessment in GD patients is advisable. Moreover, lifestyle changes and control of metabolic risk factors should be part of the therapeutic approach for GD patients, preferably by a multidisciplinary team, aimed at preventing metabolic and liver-related complications
Introduzione La malattia di Gaucher (MG) è una malattia lisosomiale ereditaria caratterizzata da accumulo di glicosfingolipidi nelle cellule del sistema reticolo-endoteliale causato da deficit dell’enzima glucocerebrosidasi. L’epato-splenomegalia, piastrinopenia e alterazioni ossee sono le principali manifestazioni della MG tipo 1, insieme ad un profilo metabolico con aumentato dispendio energetico, stato infiammatorio, insulino-resistenza ed ipolipemia. Il coinvolgimento epatico è frequente e spazia da forme benigne fino alla fibrosi epatica e cirrosi. La terapia enzimatica sostitutiva e di riduzione del substrato sono risultate efficaci sulle complicanze viscerali ed ossee e sul miglioramento della spettanza e qualità di vita. I pazienti risultano quindi esposti alle possibili complicanze di uno stile di vita inadeguato e dei fattori di rischio cardio-metabolici con potenziale ricaduta sulle complicanze metaboliche ed epatiche. Descrizione degli studi Lo studio è stato progettato per caratterizzare il profilo metabolico e l’entità della malattia epatica in una coorte di pazienti adulti con MG tipo 1 e per valutare la loro relazione con le variabili MG-relate e con lo stile di vita, in quanto le conoscenze attuali sono molto limitate. I pazienti sono stati valutati al basale e alle visite di controllo, raccogliendo dati di severità di malattia e terapia; parametri antropometrici e metabolici; lo stile di vita è stato valutato con questionari validati; la composizione corporea mediante DEXA e la malattia epatica mediante ecografia addominale, risonanza magnetica ed elastometria epatica (Fibroscan®). Studio preliminare – In una coorte di 37 pazienti con MG, la fibrosi epatica significativa, definita da valori di rigidità > 7 kPa, è stata evidenziata in una parte rilevante di pazienti (19%) ed è risultata associata con la severità di malattia e con una minore durata di terapia. Tra i pazienti stabili in terapia, la fibrosi epatica è risultata significativamente associata anche alle variabili della sindrome metabolica (MetS), suggerendo un potenziale ruolo delle comorbidità metaboliche nella progressione della malattia epatica. Studio 1 – In un sottogruppo di 20 pazienti, le comorbidità metaboliche sono ampiamente rappresentate e la steatosi epatica, definita da un CAP ≥ 250 dB/min, è stata riscontrata nel 40% dei pazienti. La steatosi è risultata associata alla MetS ma non alle variabili di severità di malattia e alla terapia. Inoltre, i pazienti con steatosi presentavano un profilo metabolico peggiore rispetto al gruppo senza steatosi. Studio 2 – Valutazione delle comorbidità metaboliche ed epatiche in relazione allo stile di vita e alla composizione corporea. Dall’analisi dei questionari sulla dieta ed attività fisica, è emersa un’elevata prevalenza di dieta non equilibrata ed inattività fisica. Lo studio della composizione corporea ha mostrato un’aumentata massa grassa e ridotta massa magra ed ossea. La dieta non equilibrata e la sedentarietà sono associate agli indici di adiposità e alle variabili della MetS, suggerendo che lo stile di vita inadeguato possa avere un ruolo sulle complicanze epato-metaboliche nei pazienti in terapia stabile. Studio 3 – Infine, è stata valutata la modifica del profilo metabolico nel tempo e gli outcomes epatici in uno studio longitudinale di follow-up. Conclusioni I fattori di rischio cardio-metabolici, la steatosi e la fibrosi epatica sono altamente prevalenti e sembrano relati allo stile di vita inadeguato nella nostra coorte di pazienti adulti con MG. Pertanto, il controllo dello stile di vita e dei fattori di rischio metabolici dovrebbero essere parte integrante della terapia, preferibilmente in ambito multidisciplinare, con lo scopo di prevenire complicanze epato-metaboliche
Caratterizzazione del profilo metabolico, dell’entità del danno epatico e dello stile di vita in una coorte di pazienti adulti con malattia di Gaucher / Simonetta Lugari , 2022 May 27. 34. ciclo, Anno Accademico 2020/2021.
Caratterizzazione del profilo metabolico, dell’entità del danno epatico e dello stile di vita in una coorte di pazienti adulti con malattia di Gaucher
LUGARI, SIMONETTA
2022
Abstract
Background Gaucher disease (GD) is a rare inherited lysosomal storage disorder, characterized by glycosphingolipids accumulation in cells of the reticulo-endothelial system due to deficiency of the lysosomal enzyme acid beta-glucosidase. Hepato-splenomegaly, cytopenia and bone disease represent the main features of type 1 GD. GD patients present a peculiar metabolic profile characterized by increased energy expenditure, systemic inflammation, peripheral insulin resistance and hypolipidemia. Liver disease is frequent and variable, ranging from benign hepatomegaly to fibrosis or cirrhosis. Enzyme replacement therapy and substrate reduction therapy have proven to be very effective on visceral and bone disease and to improve patients’ morbidity and quality of life. Aging GD patients, as the general population, may develop lifestyle-related metabolic risk factors with a potential impact on morbidity and mortality. Description of the studies Limited data are available about body composition, metabolic features, liver disease and lifestyle in GD. This project was designed to characterize the metabolic profile and the liver disease burden in a cohort of adult type 1 GD patients and to evaluate their relationship with GD variables and lifestyle. Patients were evaluated at baseline and follow-up visits, collecting data about GD severity and therapy, anthropometric and metabolic parameters; lifestyle habits were evaluated by validated questionnaires; body composition was assessed by DEXA and liver disease by abdominal ultrasound, magnetic resonance and liver transient elastometry (Fibroscan®). Preliminary study - In a cohort of 37 adult type 1 GD patients, a notable proportion (19%) showed significant liver fibrosis, defined as liver stiffness > 7 kPa, which was associated with GD severity features and a short therapy duration. Among patients on stable ERT, liver fibrosis was also significantly associated with the metabolic syndrome components, suggesting a potential role of metabolic comorbidities in liver disease progression. Study 1 – Within a subgroup of 20 patients of the cohort, metabolic comorbidities were widely represented and liver steatosis, defined as CAP value ≥ 250 dB/min, was detected in 40% of them. Significant steatosis was associated with metabolic syndrome, but not with GD severity variables and therapy duration. Moreover, patients with liver steatosis showed a worse metabolic profile and higher liver stiffness than the counterpart without steatosis. Study 2 – Then, we aimed at evaluating metabolic and liver-related comorbidities in relation to lifestyle and body composition. Analysis of the dietary and physical activity questionnaires showed, respectively, a high prevalence of unbalanced diet and physical inactivity. Body composition evaluation showed an increased fat mass and decreased bone and lean mass. Unbalanced diet and sedentariness were positively associated with indices of adiposity and metabolic syndrome features, suggesting that unhealthy lifestyle had a potential role on metabolic and liver complications in GD patients on stable ERT. Study 3 – Finally, we aimed at evaluating changes in metabolic profile over time and at identifying predictors of liver-related outcome in a longitudinal follow-up study. Conclusions Cardiometabolic risk factors, liver steatosis and fibrosis are highly prevalent and seem to be mainly related to unhealthy lifestyle in our adult GD cohort on stable therapy. For that reason, a cardiometabolic and lifestyle assessment in GD patients is advisable. Moreover, lifestyle changes and control of metabolic risk factors should be part of the therapeutic approach for GD patients, preferably by a multidisciplinary team, aimed at preventing metabolic and liver-related complicationsFile | Dimensione | Formato | |
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PhD Thesis CEM_Lugari Simonetta.pdf
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