Gaucher Disease (GD) is a lysosomal storage disorder due to biallelic loss-of-function mutations in the glucocerebrosidase (GBA1) gene leading to glycosphingolipid accumulation in cells of the reticulo-endothelial system . Hepatosplenomegaly, thrombocytopenia and bone disease are the major presenting features of type 1 GD, the most frequent chronic visceral variant . Liver involvement in type 1 GD is almost universal and ranges from hepatomegaly, with or without liver enzymes alterations, to liver fibrosis, cirrhosis, portal hypertension and hepatocellular carcinoma . GD is also characterized by peculiar metabolic abnormalities, including hypermetabolic state, peripheral insulin resistance, and dyslipidaemia with low plasma levels of high-density lipoprotein (HDL) cholesterol , owing to lysosomal dysfunction, alterations in sphingomyelin-ceramide-glycosphingolipid pathways and systemic chronic low-grade inflammation. These same pathophysiological mechanisms have been increasingly recognized in the pathogenesis of some common acquired conditions, such as obesity and metabolic syndrome (MetS) . Enzyme replacement therapy (ERT), very effective on visceral, haematological and skeletal complications of GD, has significantly improved expectancy and quality of life of type 1 GD patients, but a significant weight gain has been reported in several patients with time . Moreover, as for the general population, aging GD patients are increasingly exposed to unhealthy lifestyle, such as caloric intake excess, unbalanced diet, excessive alcohol consumption and sedentariness . Due to this background, it could be expected that the prevalence of liver steatosis in adult type 1 GD patients is remarkable.Liver steatosis is characterized by the ectopic storage of triglycerides in hepatocytes, and is mainly related to the components of the MetS, featuring metabolic dysfunction-associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease (NAFLD) . MAFLD is determined by an unbalance between the rate of hepatic triglycerides synthesis and catabolism due to an altered whole-body energetic homeostasis resulting from caloric intake exceeding caloric expenditure . Paralleling the worldwide increase in obesity, diabetes and metabolic risk abnormalities, MAFLD is the most rapidly growing cause of chronic liver disease , and is strongly associated with the risk of liver fibrosis/cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC), leading to increased liver-related morbidity and mortality . Of note, MAFLD acts synergistically with concurrent chronic liver disease to further accelerate the progression of liver injury . As a consequence, it could be hypothesized that GD patients with liver steatosis are at higher risk of developing advanced liver disease.Controlled attenuation parameter (CAP) is a recently developed non-invasive tool for qualitative and quantitative assessment of liver steatosis. CAP measures the degree of ultrasound attenuation due to hepatic fat based on signals acquired by a technology named vibration-controlled transient elastography (VCTE) implemented on Fibroscan® . Several studies have clearly shown that CAP values are strongly associated with obesity, MetS and alcohol consumption, variables epidemiologically associated with liver steatosis . Moreover, large prospective studies including patients with chronic liver diseases of various etiologies consistently reported a good correlation of CAP values with the amount of steatosis assessed by liver biopsy. Of note, since CAP is integrated in Fibroscan®, it is possible to have a one-shot reliable non-invasive assessment of both liver steatosis and fibrosis using the same equipment.In this prospective study, aimed to assess the prevalence of significant liver steatosis and to identify the factors associated with liver steatosis evaluated by VCTE with CAP in adult patients with type 1 GD from an Italian GD referral centre.

20 adult type 1 GD patients from an Italian academic referral centre were prospectively submitted to vibration controlled transient elastography (Fibroscan®) with controlled attenuation parameter (CAP); significant steatosis was defined as CAP values ≥ 250 dB/min. Results: Median CAP values were 234 [165-358] dB/min and 8 patients (40%) had significant steatosis. Significant steatosis was associated with indices of adiposity (weight, BMI and waist circumference), high blood pressure, insulin resistance and metabolic syndrome. GD-related variables and dose and duration of ERT were not associated with significant steatosis. In the subgroup of 16 patients on stable ERT for at least 24 months, CAP resulted significantly and positively associated with liver stiffness (rho 0.559, p=0.024). Significant steatosis is highly prevalent in adult type 1 GD patients and is strongly associated with a worse metabolic profile, featuring metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD may determine liver fibrosis progression in GD patients on stable ERT and may be a risk factor for long-term liver-related complications.

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Pancreatic disorders and therapy