Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?

Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage, as observed in two recessive autosomal genetic diseases, Wolman disease and Cholesterol ester storage disease. Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency. By contrast, few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene. In the last few years, a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease (NAFLD), suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease. Patients with NAFLD show a significant, progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. Among cirrhosis of different etiologies, those with cryptogenic cirrhosis show the most significant reductions of LAL activity. These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD. Moreover, the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting

Long-term prediction of adherence to continuous positive air pressure therapy for the treatment of moderate/severe obstructive sleep apnea syndrome

BACKGROUND: Continuous positive airway pressure (CPAP) therapy is a highly effective treatment for obstructive sleep apnea syndrome (OSAS). However, poor adherence is a limiting factor, and a significant proportion of patients are unable to tolerate CPAP. The aim of this study was to determine predictors of long-term non-compliance with CPAP. METHODS: CPAP treatment was prescribed to all consecutive patients with moderate or severe OSAS (AHI ≥15 events/h) (n = 295) who underwent a full-night CPAP titration study at home between February 1, 2002 and December 1, 2016. Adherence was defined as CPAP use for at least 4 h per night and five days per week. Subjects had periodical follow-up visits including clinical and biochemical evaluation and assessment of adherence to CPAP. RESULTS: Median follow-up observation was 74.8 (24.2/110.9) months. The percentage of OSAS patients adhering to CPAP was 41.4% (42.3% in males and 37.0% in females), and prevalence was significantly higher in severe OSAS than in moderate (51.8% vs. 22.1%; p < 0.001; respectively). At multivariate analysis, lower severity of OSAS (HR = 0.66; CI 95 0.46-0.94) p < 0.023), cigarette smoking (HR = 1.72; CI 95 1.13-2.61); p = 0.011), and previous cardiovascular events (HR = 1.95; CI 95 1.03-3.70; p = 0.04) were the only independent predictors of long-term non-adherence to CPAP after controlling for age, gender, and metabolic syndrome. CONCLUSIONS: In our cohort of patients with moderate/severe OSAS who were prescribed CPAP therapy, long-term compliance to treatment was present in less than half of the patients. Adherence was positively associated with OSAS severity and negatively associated with cigarette smoking and previous cardiovascular events at baseline

New insights into the pathogenesis of non-alcoholic fatty liver disease: gut-derived lipopolysaccharides and oxidative stress

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The intricate NAFLD pathogenesis is summarized by the multiple-hits hypothesis, which combines all the environmental and genetic factors that promote the development of NAFLD into a single scenario. Among these, bacterial lipopolysaccharides (LPS) are derived from the overgrowth of Gram-negative bacteria and translocated mainly as a consequence of enhanced intestinal permeability. Furthermore, oxidative stress is increased in NAFLD as a consequence of reactive oxygen species (ROS) overproduction and a shortage of endogenous antioxidant molecules, and it is promoted by the interaction between LPS and the Toll-like receptor 4 system. Interestingly, oxidative stress, which has previously been described as being overexpressed in cardiovascular disease, could represent the link between LPS and the increased cardiovascular risk in NAFLD subjects. To date, the only effective strategy for the treatment of NAFLD and non-alcoholic steatohepatitis (NASH) is the loss of at least 5% body weight in overweight and/or obese subjects. However, the dose-dependent effects of multispecies probiotic supplementation on the serum LPS level and cardiometabolic profile in obese postmenopausal women were demonstrated. In addition, many antibiotics have regulatory effects on intestinal microbiota and were able to reduce serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor alpha (TNF-α) in NASH animal models. Regarding the oxidant status, a Mediterranean diet has been reported to reduce oxidant stress, while vitamin E at high daily dosages induced the resolution of NASH in 36% of treated patients. Silymarin had the positive effect of reducing transaminase levels in NAFLD patients and long-term treatment may also decrease fibrosis and slow liver disease progression in NASH. Finally, the influence of nutraceuticals on gut microbiota and oxidant stress in NAFLD patients has not yet been well elucidated and there are insufficient data either to support or refuse their use in these subjects

Sex-related differences in the association between metabolic syndrome and gallstone disease

Metabolic syndrome (MetS) and gallstone disease (GD) share common risk factors. Several epidemiological studies reported that subjects with Mets are more likely to have GD than those without and that cholecystectomy (CHO) may increase the risk of MetS. The aim of the study was to evaluate the association between MetS and GD in a large cohort of patients with metabolic risk factors in Italy. The study was performed in 620 consecutive outpatients referring to the University outpatients’ clinic for the management of cardiovascular risk factors. MetS were diagnosed according to the ATPIII Expert Panel modified criteria. GD was defined as gallstones documented by abdominal ultrasound (US) or previous cholecystectomy. The prevalence of GD was significantly higher in women than in men (22.3% vs. 13.1%, p = 0.003). Both prevalence of GD (17.1% vs. 8.4%, p = 0.015) and CHO (9.0% vs. 1.7%, p = 0.002) were significantly higher in males with MetS as compared to those without. By contrast, the prevalence of GD and of CHO was similar in women with and without MetS. After correction for confounders, MetS was an independent predictor of both GD (odds ratio (OR) 1.943, p = 0.048) and CHO (OR 5.075, p = 0.011) in men, but not in women. In conclusion, in this study, including western subjects with cardiometabolic risk factors, the association between GD, prior CHO and MetS were found in men, but not in women

D-dimer for risk stratification and antithrombotic treatment management in acute coronary syndrome patients: asystematic review and metanalysis

Background: Data on the prognostic role of D-dimer in patients with acute coronary syndrome (ACS) are controversial. Our aim was to summarize current evidence on the association between D-dimer levels and short/long-term poor prognosis of ACS patients. We also investigated the association between D-dimer and no-reflow phenomenon.Methods: Systematic review and metanalysis of observational studies including ACS patients and reporting data on D-dimer levels. PubMed and SCOPUS databases were searched. Data were combined with hazard ratio (HR) and metanalysed. The principal endpoint was a composite of cardiovascular events (CVEs) including myocardial infarction, all-cause and cardiovascular mortality.Results: Overall, 32 studies included in the systematic review with 28,869 patients. Of them, 6 studies investigated in-hospital and 26 studies long-term outcomes. Overall, 23 studies showed positive association of high D-dimer levels with CVEs. D-dimer levels predicted poor prognosis in all studies reporting in-hospital outcomes. Five studies satisfied inclusion criteria and were included in the metanalysis, with a total of 8616 patients. Median follow-up was 13.2 months with 626 CVEs. The pooled HR for D-dimer levels and CVEs was 1.264 (95% CI 1.134-1.409). Five out of 7 studies (4195 STEMI patients) investigating the association between D-dimer levels and no-reflow showed a positive correlation of D-dimer levels with no-reflow.Conclusions: In patients with ACS, D-dimer was associated with higher in-hospital and short/long-term complications. D-dimer was also higher in patients with no-reflow phenomenon. The use of D-dimer may help to identify patients with residual thrombotic risk after ACS

Von willebrand and factor VIII portosystemic circulation gradient in cirrhosi. Implications for portal vein thrombosis

OBJECTIVES: Portal vein thrombosis seems to be dependent on local hypercoagulation and venous stasis; data regarding endothelial damage are lacking. METHODS: von Willebrad factor, a marker of endothelial damage/perturbation, factor VIII, and lipopolysaccharides (LPS) were studied in the portal and systemic circulation of 20 cirrhotic patients undergoing transjugular intrahepatic portosystemic procedure. RESULTS: von Willebrad factor, factor VIII, and LPS were higher in the portal compared with systemic circulation, with a significant correlation between LPS and the other 2 variables. DISCUSSION: Endothelial damage and hypercoagulation coexist in the portal tree of patients with cirrhosis, and both could contribute to portal vein thrombosis. LPS may be a potential trigger of endothelial damage

SEISMIC ANISOTROPY AND MICRO-SEISMICITY IN THE UPPER CRUST AT NORTH OF GUBBIO BASIN (CENTRAL ITALY): RELATION WITH THE SUBSURFACE GEOLOGICAL STRUCTURES AND THE ACTIVE STRESS FIELD

During the months of April and May 2010, a seismic sequence (here named “Pietralunga seismic sequence”) took place in the northeastern part of the Gubbio basin (Northern Apennines); this area is well known to be interested by a continuous background micro-seismic activity. The sequence was recorded both by the INGV National Seismic Network, and by the stations installed by the Project “AIRPLANE” (financially supported by MIUR-Italian Ministry of Education and Research) with the aim of investigating the seismogenetic processes in the Alto Tiberina Fault (ATF) system region. In this work we present the anisotropic results at four stations: ATFO, ATPC, ATPI, ATVO located around the northern termination of the Gubbio basin that well delimit both the seismic se- quence and the whole 2010 seismicity (about 2500 events). The study of seismic anisotropy has provided useful information for the interpretation and evaluation of the stress field and active crustal deformation. Seismic anisotropy can yield valuable information on upper crustal structure, fracture field, and presence of fluid-saturated rocks. Moreover, the large number of seismic waveforms recorded especially during the Pietralunga sequence allows us also to study the spatio-temporal changes of anisotropic parameters to better understand its evolution and the possible correlation to the presence and migration of fluids