Lipid-based insulin-resistance markers predict cardiovascular events in metabolic dysfunction associated steatotic liver disease.

BACKGROUND: Insulin resistance (IR) is the cornerstone of Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD), pathophysiologically being the key link between MASLD, metabolic disorders, and cardiovascular (CV) diseases. There are no prospective studies comparing the predictive values of different markers of insulin resistance (IR) in identifying the presence of MASLD and the associated risk of cardiovascular events (CVEs). METHODS: Post hoc analysis of the prospective Plinio Study, involving dysmetabolic patients evaluated for the presence of MASLD. The IR markers considered were Homeostatic Model Assessment for IR (HOMA-IR), Triglycerides-Glycemia (TyG) index, Triglycerides to High-Density Lipoprotein Cholesterol ratio (TG/HDL-C), Lipid Accumulation Product (LAP) and Visceral Adiposity Index (VAI). Receiver operative characteristic (ROC) analyses were performed to find the optimal cut-offs of each IR marker for detecting MASLD and predicting CVEs in MASLD patients. Logistic and Cox multivariable regression analyses were performed, after dichotomizing the IR markers based on the optimal cut-offs, to assess the factors independently associated with MASLD and the risk of CVEs. RESULTS: The study included 772 patients (age 55.6 ± 12.1 years, 39.4% women), of whom 82.8% had MASLD. VAI (Area Under the Curve [AUC] 0.731), TyG Index (AUC 0.723), and TG/HDL-C ratio (AUC: 0.721) predicted MASLD but was greater with HOMA-IR (AUC: 0.792) and LAP (AUC: 0.787). After a median follow-up of 48.7 (25.4-75.8) months, 53 MASLD patients experienced CVEs (1.8%/year). TyG index (AUC: 0.630), LAP (AUC: 0.626), TG/HDL-C (AUC: 0.614), and VAI (AUC: 0.590) demonstrated comparable, modest predictive values in assessing the CVEs risk in MASLD patients. CONCLUSION: In dysmetabolic patients HOMA-IR and LAP showed the best accuracy in detecting MASLD. The possible use of lipid-based IR markers in stratifying the CV risk in patients with MASLD needs further validation in larger cohorts.

PAD4-Induced NETosis Via Cathepsin G-Mediated Platelet-Neutrophil Interaction in ChAdOx1 Vaccine-Induced Thrombosis-Brief Report.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare syndrome characterized by platelet anti-PF4 (platelet-activating antiplatelet factor 4)-related thrombosis. Platelet-neutrophil interaction has been suggested to play a role, but the underlying mechanism has not been fully elucidated. METHODS: The study included 10 patients with VITT after ChAdOx1 (chimpanzee adenovirus Oxford 1) nCoV-19 (Oxford-AstraZeneca) vaccine administration, 10 patients with ischemic stroke (IS), 10 patients with acute deep vein thrombosis, and 10 control subjects in whom blood levels of neutrophil extracellular traps (NETs), soluble TF (tissue factor), and thrombin generation were examined. Furthermore, we performed in vitro studies comparing the effect of serum from patients and controls on NETs formation. Finally, immunohistochemistry was performed in cerebral thrombi retrieved from a patients with VITT and 3 patients with IS. RESULTS: Compared with patients with IS, patients with deep vein thrombosis, controls, and patients with VITT had significantly higher blood values of CitH3 (citrullinated histone H3), soluble TF, D-dimer, and prothrombin fragment 1+2 (P<0.0001). Blood CitH3 significantly correlated with blood soluble TF (Spearman rank correlation coefficient=0.7295; P=0.0206) and prothrombin fragment 1+2 (Spearman rank correlation coefficient=0.6809; P<0.0350) in patients with VITT. Platelet-neutrophil mixture added with VITT plasma resulted in higher NETs formation, soluble TF and thrombin generation, and platelet-dependent thrombus growth under laminar flow compared with IS and deep vein thrombosis plasma; these effects were blunted by PAD4 (protein arginine deiminase 4) and cathepsin G inhibitors, anti-FcγRIIa (Fc receptor for IgG class IIa), and high doses of heparin. Immunohistochemistry analysis showed a more marked expression of PAD4 along with more diffuse neutrophil infiltration and NETs formation as well as TF and cathepsin expression in VITT thrombus compared with thrombi from patients with IS. CONCLUSIONS: Patients with VITT display enhanced thrombogenesis by PAD4-mediated NETs formation via cathepsin G-mediated platelet/neutrophil interaction.

Cholesterol Remnants, Triglyceride-Rich Lipoproteins and Cardiovascular Risk.

Randomized clinical trials with statins and other lipid-lowering drugs have shown the presence of a "residual cardiovascular risk" in those treated to "target" for LDL-cholesterol. This risk is mainly associated to lipid components other than LDL and in particular to remnant cholesterol (RC) and to lipoproteins rich in triglycerides in fasting and non-fasting conditions. During fasting, RCs correspond to the cholesterol content of the VLDL and their partially depleted triglyceride remnant containing apoB-100. Conversely, in non-fasting conditions, RCs include also cholesterol present in chylomicrons containing apoB-48. Therefore, RCs refer to total plasma cholesterol minus HDL-cholesterol and LDL-cholesterol, that is, all the cholesterol present in the VLDL, chylomicrons and in their remnants. A large body of experimental and clinical data suggests a major role of RCs in the development of atherosclerosis. In fact, RCs easily pass the arterial wall and bind to the connective matrix stimulating the progression of smooth muscle cells and the proliferation of resident macrophages. RCs are a causal risk factor for cardiovascular events. Fasting and non-fasting RCs are equivalent for predicting vascular events. Further studies on drugs effect on RC levels and clinical trials to evaluate the efficacy of RC reduction on cardiovascular events are needed.

Statin liver safety in non-alcoholic fatty liver disease: A systematic review and metanalysis.

AIMS: Statin liver safety in non-alcoholic fatty liver disease (NAFLD) patients is not well defined. We analysed differences in liver function tests, including alanine transaminase aminotransferase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT) in NAFLD patients treated or not treated with statins. METHODS: We performed a systematic review of MEDLINE via PubMed and EMBASE databases and metanalysis of clinical studies investigating levels of ALT, AST and GGT in NAFLD according to statin treatment. Mean difference (MD) and percentage MD were calculated between the two groups. RESULTS: We included 22 studies with 2345 NAFLD patients. Overall, 16 were before-after interventional, five were cross-sectional and one was combined cross-sectional/interventional study. In all interventional studies, except one, patients had raised ALT, AST and GGT at baseline. Interventional studies showed reduced ALT values with an MD reduction of -27.2 U/L (95% CI -35.25/-19.15) and a percentage MD reduction of -35.41% (95% CI -44.78/-26.04). Also, AST values were reduced after statin treatment in interventional studies with an MD of -18.82 U/L (95% CI -25.63/-12.02) (percentage -31.78%, 95% CI -41.45/-22.11). Similarly, GGT levels were reduced after statin treatment with an MD of -19.93 U/L (95% CI -27.10/-12.77) (percentage -25.57%, 95% CI -35.18/-15.97). Cross-sectional studies showed no difference in AST and GGT values between patients treated with and without statins. CONCLUSION: In interventional studies, ALT, AST and GGT were reduced after statin treatment with a percentage mean difference of -35.41%, -31.78% and -25.57%, respectively, while observational studies showed a null effect, suggesting liver safety of statins in NAFLD patients.

Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD.

BACKGROUND AND AIMS: Lipopolysaccharides (LPS) is increased in nonalcoholic fatty liver disease (NAFLD), but its relationship with liver inflammation is not defined. APPROACH AND RESULTS: We studied Escherichia coli LPS in patients with biopsy-proven NAFLD, 25 simple steatosis (nonalcoholic fatty liver) and 25 nonalcoholic steatohepatitis (NASH), and in mice with diet-induced NASH. NASH patients had higher serum LPS and hepatocytes LPS localization than controls, which was correlated with serum zonulin and phosphorylated nuclear factor-κB expression. Toll-like receptor 4 positive (TLR4+ ) macrophages were higher in NASH than simple steatosis or controls and correlated with serum LPS. NASH biopsies showed a higher CD61+ platelets, and most of them were TLR4+ . TLR4+ platelets correlated with serum LPS values. In mice with NASH, LPS serum levels and LPS hepatocyte localization were increased compared with control mice and associated with nuclear factor-κB activation. Mice on aspirin developed lower fibrosis and extent compared with untreated ones. Treatment with TLR4 inhibitor resulted in lower liver inflammation in mice with NASH. CONCLUSIONS: In NAFLD, Escherichia coli LPS may increase liver damage by inducing macrophage and platelet activation through the TLR4 pathway.

Statin use and mortality in atrial fibrillation: A systematic review and meta-analysis of 100,287 patients.

Statins are effective for reducing cardiovascular disease in patients at risk or with cardiovascular disease. The benefit of statin therapy on adverse cardiovascular outcomes in patients with non-valvular atrial fibrillation (AF) is not clear. We performed a systematic review and meta-analysis of studies retrieved from MEDLINE via PubMed and Cochrane (CENTRAL) database of studies investigating the efficacy of statins in AF patients. The principal endpoint was all-cause mortality. Other endpoints were cardiovascular mortality, ischemic stroke, composite endpoints and any bleeding. We included 14 studies (2 post-hoc analysis of randomized clinical trials, 8 prospective and 4 retrospective) with 100,287 AF patients, of whom 23,228 were on statins. The pooled hazard ratio (HR) for all-cause mortality was 0.59 (95 % Confidence Interval [CI] 0.54-0.65). This association was consistent by aging, sex and prevalent cardiovascular or cerebrovascular disease. and the beneficial effect was evident already after 12 months of therapy. The absolute risk reduction for all-cause mortality in patients treated with statins was 10 % (95 % CI 9-10). The pooled HR for statins against cardiovascular mortality was 0.75 (95 % CI 0.58-0.96). No association was found with other secondary endpoints. Regarding bleeding events, the pooled HR for statin use was 0.60 (95 % CI 0.48-0.76). Our meta-analysis shows that in AF patients, statin therapy was associated with a reduction in all-cause and cardiovascular mortality are reduced by 41 % and 25 %, respectively. Randomized clinical trials in AF patients are necessary, as well as clarity on AF-specific LDL cholesterol targets.

Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors Reduce Platelet Activation Modulating ox-LDL Pathways.

Background: Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) lower LDL-cholesterol and slow atherosclerosis preventing cardiovascular events. While it is known that circulating PCSK9 enhances platelet activation (PA) and that PCSK9i reduce it, the underlying mechanism is not still clarified. Methods: In a multicenter before-after study in 80 heterozygous familial hypercholesterolemia (HeFH) patients on treatment with maximum tolerated statin dose ± ezetimibe, PA, soluble-NOX2-derived peptide (sNOX2-dp), and oxidized-LDL (ox-LDL) were measured before and after six months of PCSK9i treatment. In vitro study investigates the effects of plasma from HeFH patients before and after PCK9i on PA in washed platelets (wPLTs) from healthy subjects. Results: Compared to baseline, PCSK9i reduced the serum levels of LDL-c, ox-LDL, Thromboxane (Tx) B2, sNOX2-dp, and PCSK9 (p < 0.001). The decrease of TxB2 correlates with that of ox-LDL, while ox-LDL reduction correlated with PCSK9 and sNOX2-dp delta. In vitro study demonstrated that wPLTs resuspended in plasma from HeFH after PCSK9i treatment induced lower PA and sNOX2-dp release than those obtained using plasma before PCSK9i treatment. This reduction was vanished by adding ox-LDL. ox-LDL-induced PA was blunted by CD36, LOX1, and NOX2 inhibition. Conclusions: PCSK9i treatment reduces PA modulating NOX2 activity and in turn ox-LDL formation in HeFH patients.

Nonalcoholic Fatty Liver Disease and Fibrosis Associated With Increased Risk of Cardiovascular Events in a Prospective Study.

BACKGROUND & AIMS: Patients with non-alcoholic fatty liver disease (NAFLD) are at increased chance for cardiovascular events (CVEs). Severity of liver fibrosis is used to determine prognoses for patients with NAFLD, but little is known about the relationship between liver fibrosis and CVEs in the real world. METHODS: We analyzed data from the prospective observational progression of liver damage and cardiometabolic disorders in non-alcoholic fatty liver disease study, comprising 898 consecutive outpatients (mean age, 56.4 ± 12.7 years; 37.5% women) screened for liver steatosis by ultrasound according to Hamagughi criteria. Liver fibrosis was defined as FIB-4 score greater than 2.67 and NAFLD fibrosis score greater than 0.676. After enrolment, patients were interviewed by phone every 6 months and examined every 12 months in the outpatient clinic, and CVEs were recorded (fatal or nonfatal ischemic stroke and myocardial infarction, cardiac or peripheral revascularization, new-onset arterial fibrillation and cardiovascular death). The primary outcomes were incidence rate of CVEs in patients with vs without NAFLD and factors associated with CVEs in patients with NAFLD. RESULTS: Over a median follow-up time of 41.4 months (3044.4 patient-years), 58 CVEs (1.9%/year) were registered. The rate of CVEs was higher in patients with (n = 643, 2.1%/year) vs without NAFLD (n = 255, 1.0%/year) (P = .066). In multivariable Cox proportional regression analysis, NAFLD increased risk for CVEs (hazard ratio [HR], 2.41; 95% CI, 1.06-5.47; P = .036), after adjustment for metabolic syndrome. Among patients with NAFLD, male sex, previous CVEs, metabolic syndrome and FIB-4 scores greater than 2.67 (HR, 4.02; 95% CI, 1.21-13.38; P = .023) were independently associated with risk of incident CVEs. NFS scores greater than 0.676 were also independently associated with risk of incident CVEs (HR, 2.35; 95% CI, 1.05-5.27; P = .038). CONCLUSIONS: In an analysis of data from a study of patients screened for NAFLD and followed, individuals with NAFLD had more than a 2-fold increase in risk of CVEs, and those with liver fibrosis had a 4-fold increase in risk. In patients with NAFLD, liver fibrosis indexes were independently associated with risk of incident CVEs. ClinicalTrials.gov no:NCT04036357.

Incidence of Post-Implantation Syndrome with Different Endovascular Aortic Aneurysm Repair Modalities and Devices and Related Etiopathogenetic Implications.

BACKGROUND: Postimplantation syndrome (PIS) is a systemic inflammatory response occurring in an early phase after abdominal aortic aneurysm (AAA) endovascular aneurysm repair (EVAR). The pathophysiology underlying PIS is still not well understood. It is speculated that the type of the stent graft or the mural thrombus within the AAA may play a role in determining this inflammatory response. At present, there is no consensus about the influence of PIS on clinical outcomes during follow-up. The endovascular aneurysm sealing (EVAS) with the Nellix sac-anchoring endoprosthesis (Nellix Endovascular, Palo Alto, CA) is a novel modality for AAA repair, which obliterates the sac, thus preventing the new onset of thrombus in the aneurysm sac. Our aim was to compare the incidence of postimplantation syndrome following EVAS and after EVAR. Secondary aims were to assess the effect of endoskeleton AFX (Endologix) device compared with other commercially available exoskeleton PTFE stent grafts on the inflammatory response. Finally, we analyzed the potential association of PIS with clinical outcomes. METHODS: From January 2013 to June 2018, 60 AAA patients underwent EVAS (mean age 72 ± 9 years), and 110 patients were submitted to EVAR: 56 AFX devices and 54 other PTFE stent grafts (mean age 74 ± 10 years) at a single center and were retrospectively reviewed. RESULTS: EVAS with the Nellix system was associated with a lower incidence of PIS compared to EVAR using both AFX device and other endografts (8.3, 30, 35%, respectively, P-value = 0.001). No statistically significant difference in PIS incidence was observed after endoskeleton AFX device deployment compared with other EVAR exoskeleton endografts. During follow up, the major complications were proportionally but not significantly (P = 0.43) less frequent after EVAS (10.3%) than after EVAR and after EVAR using AFX device (8.9%) than after EVAR with other PTFE stent grafts (16.4%). During follow up (mean 24 months), adverse outcome rates did not significantly differ in patients with and without PIS (8.0 vs. 13.4% P = 0.43). CONCLUSIONS: Our data confirm the lower risk of PIS following EVAS compared to EVAR. Most importantly, this study highlights the role of new-onset mural thrombus in the genesis of PIS. The lower inflammatory reaction observed after EVAS than after EVAR might be related to the endobags of the Nellix system, which completely seal the aneurysm sac, reducing the new onset of mural thrombus. The systemic inflammatory response does not significantly differ after endoskeleton AFX device deployment compared with other EVAR exoskeleton stent grafts. PIS does not seem to have any significant prognostic implications in terms of early major adverse events.

Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Recent evidence showed a reduced activity of the lysosomal acid lipase (LAL) in patients with non-alcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC). However, the relationship between LAL activity and liver fibrosis has never been investigated. METHODS: Cross-sectional study including 575 outpatients referred for the management of cardio-metabolic and liver disease. The absence of liver fibrosis was defined by a FIB-4 < 1.30 and NAFLD fibrosis score (NFS) <-1.455. LAL activity was measured with dried blood spot technique. RESULTS: Overall, 515 patients had a diagnosis of NAFLD (454 NAFL and 61 biopsy-proven NASH) and 60 of CC. The value of LAL activity progressively decreased from healthy subjects to NAFL/NASH patients to CC (P < .001). LAL activity was reduced by 10% in patients with NAFL, by 20% in NASH and by 50% in CC. The prevalence of CC decreased across the tertiles of LAL activity: 22.2% in the lowest, 4.6% in the intermediate and 0.5% in the highest tertile. In NAFLD patients, 69.9% had a FIB4 < 1.30, and 43.1% a NFS <-1.455. Multivariate logistic regression analysis showed that Log (LAL activity) was associated with FIB-4 < 1.30 (Odds ratio [OR] 2.19 95% confidence interval [CI] 1.33-3.62, P = .002) and NFS < -1.455 (OR 2.43, 95% CI 1.51-3.91, P < .001) after adjustment for confounding factors. CONCLUSIONS: We found a progressive reduction of LAL activity according to liver disease severity. LAL activity was inversely associated with markers of liver fibrosis in patients with NAFLD.

Severity of OSAS, CPAP and cardiovascular events: A follow-up study.

BACKGROUND: Previous studies suggested obstructive sleep apnoea syndrome (OSAS) as a major risk factor for incident cardiovascular events. However, the relationship between OSAS severity, the use of continuous positive airway pressure (CPAP) treatment and the development of cardiovascular disease is still matter of debate. STUDY OBJECTIVES: The aim was to test the association between OSAS and cardiovascular events in patients with concomitant cardio-metabolic diseases and the potential impact of CPAP therapy on cardiovascular outcomes. METHODS: Prospective observational cohort study of consecutive outpatients with suspected metabolic disorders who had complete clinical and biochemical workup including polysomnography because of heavy snoring and possible OSAS. The primary endpoint was a composite of major adverse cardiovascular and cerebrovascular events (MACCE). RESULTS: Median follow-up was 81.3 months, including 434 patients (2701.2 person/years); 83 had a primary snoring, 84 had mild, 93 moderate and 174 severe OSAS, respectively. The incidence of MACCE was 0.8% per year (95% confidence interval [CI] 0.2-2.1) in primary snorers and 2.1% per year (95% CI 1.5-2.8) for those with OSAS. A positive association was observed between event-free survival and OSAS severity (log-rank test; P = .041). A multivariable Cox regression analysis showed obesity (HR = 8.011, 95% CI 1.071-59.922, P = .043), moderate OSAS (vs non-OSAS HR = 3.853, 95% CI 1.069-13.879, P = .039) and severe OSAS (vs non-OSAS HR = 3.540, 95% CI 1.026-12.217, P = .045) as predictors of MACCE. No significant association was observed between CPAP treatment and MACCE (log-rank test; P = .227). CONCLUSIONS: Our findings support the role of moderate/severe OSAS as a risk factor for incident MACCE. CPAP treatment was not associated with a lower rate of MACCE.

Overexpression of the Vitronectin V10 Subunit in Patients with Nonalcoholic Steatohepatitis: Implications for Noninvasive Diagnosis of NASH.

Nonalcoholic steatohepatitis (NASH) is the critical stage of nonalcoholic fatty liver disease (NAFLD). The persistence of necroinflammatory lesions and fibrogenesis in NASH is the leading cause of liver cirrhosis and, ultimately, hepatocellular carcinoma. To date, the histological examination of liver biopsies, albeit invasive, remains the means to distinguish NASH from simple steatosis (NAFL). Therefore, a noninvasive diagnosis by serum biomarkers is eagerly needed. Here, by a proteomic approach, we analysed the soluble low-molecular-weight protein fragments flushed out from the liver tissue of NAFL and NASH patients. On the basis of the assumption that steatohepatitis leads to the remodelling of the liver extracellular matrix (ECM), NASH-specific fragments were in silico analysed for their involvement in the ECM molecular composition. The 10 kDa C-terminal fragment of the ECM protein vitronectin (VTN) was then selected as a promising circulating biomarker in discriminating NASH. The analysis of sera of patients provided these major findings: the circulating VTN fragment (i) is overexpressed in NASH patients and positively correlates with the NASH activity score (NAS); (ii) originates from the disulfide bond reduction between the V10 and the V65 subunits. In conclusion, V10 determination in the serum could represent a reliable tool for the noninvasive discrimination of NASH from simple steatosis.

Adherence to Mediterranean Diet and Non-Alcoholic Fatty Liver Disease: Effect on Insulin Resistance.

OBJECTIVES: The prevalence of cardiometabolic disorders, including non-alcoholic fatty liver disease (NAFLD), is increasing in western countries, because of changes in lifestyle and dietary habits. Mediterranean Diet (Med-Diet) is effective for cardiovascular prevention, but its relationship with NAFLD has been scarcely investigated. METHODS: We included 584 consecutive outpatients presenting with one or more cardiovascular risk factor such as type 2 diabetes mellitus (T2DM), arterial hypertension, overweight/obesity, and dyslipidemia. Liver steatosis was assessed using ultrasonography. Med-Diet adherence was investigated by a validated semiquantitative nine-item dietary questionnaire; patients were divided into low, intermediate, and high adherence. Insulin resistance was defined by the 75th percentile of homeostasis model of insulin resistance (HOMA-IR; ≥3.8). RESULTS: The mean age was 56.2±12.4 years and 38.2% were women. Liver steatosis was present in 82.7%, and its prevalence decreased from low to high adherence group (96.5% vs. 71.4%, P<0.001). In a multiple logistic regression analysis, hypertriglyceridemia (odds ratio (OR): 2.913; P=0.002), log (ALT) (OR: 6.186; P<0.001), Med-Diet adherence (intermediate vs. low OR: 0.115; P=0.041, high vs. low OR: 0.093; P=0.030), T2DM (OR: 3.940; P=0.003), and high waist circumference (OR: 3.012; P<0.001) were associated with NAFLD. Among single foods, low meat intake (OR: 0.178; P<0.001) was inversely significantly associated with NAFLD. In 334 non-diabetic NAFLD patients, age (OR: 1.035, P=0.025), high waist circumference (OR: 7.855, P<0.001), hypertriglyceridemia (OR: 2.152, P=0.011), and Log (ALT) (OR: 2.549, P=0.002) were directly associated with HOMA-IR, whereas Med-Diet score was inversely associated (OR: 0.801, P=0.018). CONCLUSIONS: We found an inverse relationship between Med-Diet and NAFLD prevalence. Among NAFLD patients, good adherence to Med-Diet was associated with lower insulin resistance. Our findings suggest that Med-Diet may be a beneficial nutritional approach in NAFLD patients.

The role of nutraceuticals for the treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to liver fibrosis and to cirrhosis. NAFLD is considered as the hepatic component of the metabolic syndrome but mechanisms underlying the onset and progression of NAFLD are still under investigation. The traditional 'two hit hypothesis' has been developed within a more complex 'multiple parallel hit hypothesis' which comprises a wide spectrum of parallel hits. Many therapeutic approaches have been proposed so far and several types of nutraceuticals have been suggested for the treatment of NAFLD and non-alcoholic steatohepatitis (NASH), the most promising of which are those with antioxidant effects. In particular, vitamin E appears to be effective for the treatment of nondiabetic subjects with more advanced NASH, although the high suggested daily dosages are a matter of concern. Moreover, polyphenols reduce liver fat accumulation, mainly by inhibiting lipogenesis. At present, there are insufficient data to support the use of vitamin C supplements in patients with NAFLD. Data on polyunsaturated fatty acid (PUFA) supplementation are heterogeneous, and no well-designed randomized controlled studies (RCTs) of adequate size, with histological assessment of steatosis, have been conducted. Based on the available data, silymarin supplementation for the treatment of NAFLD seems to have a favourable effect. The results with anti-inflammatory agents, such as vitamin D and carnitine are uncertain. In conclusion, there are insufficient data either to support or refute the use of nutraceuticals for subjects with NAFLD. Further RTCs, with histological changes as an outcome measure, are needed.

Does Lysosomial Acid Lipase Reduction Play a Role in Adult Non-Alcoholic Fatty Liver Disease?

Lysosomal Acid Lipase (LAL) is a key enzyme involved in lipid metabolism, responsible for hydrolysing the cholesteryl esters and triglycerides. Wolman Disease represents the early onset phenotype of LAL deficiency rapidly leading to death. Cholesterol Ester Storage Disease is a late onset phenotype that occurs with fatty liver, elevated aminotransferase levels, hepatomegaly and dyslipidaemia, the latter characterized by elevated LDL-C and low HDL-C. The natural history and the clinical manifestations of the LAL deficiency in adults are not well defined, and the diagnosis is often incidental. LAL deficiency has been suggested as an under-recognized cause of dyslipidaemia and fatty liver. Therefore, LAL activity may be reduced also in non-obese patients presenting non-alcoholic fatty liver disease (NAFLD), unexplained persistently elevated liver transaminases or with elevation in LDL cholesterol. In these patients, it could be indicated to test LAL activity. So far, very few studies have been performed to assess LAL activity in representative samples of normal subjects or patients with NAFLD. Moreover, no large study has been carried out in adult subjects with NAFLD or cryptogenic cirrhosis.

NOX2-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non-alcoholic fatty liver disease.

BACKGROUND: Chronic oxidative stress is one of the key mechanisms responsible for disease progression in non-alcoholic fatty liver disease. However, so far, few studies reported increased circulating levels of oxidative stress markers in patients with non-alcoholic fatty liver and no study has been performed with newer markers of systemic oxidative stress. The aim was to assess the relationship between urinary 8-iso-prostaglandin F2α and serum soluble NOX2-derived peptide and the severity of liver steatosis in subjects with non-alcoholic fatty liver. METHODS: The study was performed in 264 consecutive patients referred for suspected metabolic disease. Steatosis was defined according to Hamaguchi ultrasonographic criteria. Oxidative stress was assessed by urinary 8-iso- prostaglandin F2α and serum soluble NOX2-derived peptide levels. RESULTS: Patients with non-alcoholic fatty liver had higher (p < 0.001) mean values of urinary 8-iso-PGF2α and of serum soluble NOX2-derived peptide, alanine aminotransferase, Cytokeratin-18 and homeostasis model of insulin resistance and lower values of serum adiponectin as compared to those without. Prevalence of metabolic syndrome and of its clinical features was significantly higher in patients with non-alcoholic fatty liver. Same findings were also observed after the exclusion of obese subjects, or subjects with diabetes or with metabolic syndrome and in those not taking statin medication. In addition, the levels of urinary 8-iso-PGF2α were independent predictors of non-alcoholic fatty liver and a strong association of urinary 8-iso-PGF2α and of serum soluble NOX2-derived peptide with the severity of steatosis at ultrasound was also observed. CONCLUSIONS: We demonstrated increased markers of oxidative stress in subjects with non-alcoholic fatty liver. Urinary 8-iso-PGF2α and serum soluble NOX2-derived peptide levels were independent from obesity, diabetes and metabolic syndrome and increased with the severity of liver steatosis at ultrasound.

Risk of adverse events in anticoagulated patients with atrial fibrillation and non-alcoholic fatty liver disease.

BACKGROUND: The clinical impact of Nonalcoholic fatty liver disease(NAFLD) in patients with atrial fibrillation(AF) is still controversial. AIM: To evaluate the 1-year risk of all-cause death, thromboembolic events, and bleeding in AF-NAFLD patients. METHODS: Retrospective study with a health research network(TriNetX). AF patients on oral anticoagulation(OAC) were categorized according to the presence of NAFLD into two groups. The primary outcomes were the 1-year risks of: i) a composite cardiovascular outcome (all-cause death, myocardial infarction, stroke, cardiac arrest, and pulmonary embolism); and ii) a composite hemorrhagic outcome(intracranial hemorrhage and gastrointestinal bleeding). Cox regression analysis before and after propensity-score-matching(PSM) was used to estimate Hazard Ratio(HR) and 95% confidence intervals(95%CI). Sensitivity analyses investigated the risk associated with cirrhosis, thrombocytopenia, and type of OAC(warfarin vs non-vitamin K antagonist oral anticoagulants(NOAC). RESULTS: We identified 22,636 AF-NAFLD patients (69±12 years, 46.7% females) and 391,014 AF patients without liver disease(72±12 years, 42.7% females). NAFLD was associated with a higher risk of composite cardiovascular (HR 1.54,95%CI 1.47-1.61) and hemorrhagic (HR 1.56,95%CI 1.42-1.72) outcomes. This was consistent also for all the single outcomes. Cirrhotic and thrombocytopenic AF-NAFLD patients showed the highest risks. Compared to AF-NAFLD patients on NOAC, those on warfarin were associated with a higher risk of cardiovascular and hemorrhagic outcomes. CONCLUSION: In AF patients, NAFLD is associated with a higher 1-year risk of adverse events, with the risk of adverse events progressively increasing from non-cirrhotic to cirrhotic and from non-thrombocytopenic to thrombocytopenic patients. NOACs were associated with a better effectiveness and safety profile compared to warfarin.

Impact of Sodium Glucose Cotransporter 2 Inhibitors (SGLT2i) Therapy on Dementia and Cognitive Decline.

Dementia is an age-related syndrome characterized by the progressive deterioration of cognition and capacity for independent living. Diabetes is often associated with cognitive decline and shares similar pathophysiological mechanisms with dementia, such as systemic inflammation, oxidative stress, insulin resistance, and advanced glycation end-products formation. Therefore, adequate diabetes management may reduce the risk of cognitive decline, especially in patients with other comorbidities and risk factors. The sodium glucose cotransporter inhibitors (SGLT2i) regulate renal glucose reabsorption by blocking the SGLT2 cotransporters located in the proximal tubules, causing glycosuria and intraglomerular pressure reduction. Their use helps to lower blood pressure by modifying sodium and water homeostasis; these drugs are also commonly used in the treatment of heart failure and chronic kidney disease, while recently, a potential neuroprotective role in the central nervous system has been suggested. The aim of our scoping review is to analyze current evidence about the potential neuroprotective effects of SGLT2i in adult patients. We performed a scoping literature review to evaluate the effect of SGLT2i on dementia, mild cognitive impairment (MCI) and Alzheimer's disease incidence and progression. The screening process was performed through different searches on PubMed and EMBASE, evaluating original works published up to January 2024. In conclusion, the use of SGLT2i could be associated with a neuroprotective effect in patients with diabetes, reducing the incidence or the progression of MCI and dementia. Further prospective studies are needed to validate this hypothesis and to evaluate the effectiveness of this class of drugs in normal glycemic profile patients.