Francesco Baratta

Oxidative stress mediated arterial dysfunction in patients with obstructive sleep apnoea and the effect of continuous positive airway pressure treatment

BackgroundSeveral studies suggest an increase of oxidative stress and a reduction of endothelial function in obstructive sleep apnoea syndrome (OSAS). We assessed the association between OSAS, endothelial dysfunction and oxidative stress. Further aim was to evaluate the effect of nasal continuous positive airway pressure (nCPAP) on oxidative stress and arterial dysfunction.MethodsWe studied 138 consecutive patients with heavy snoring and possible OSAS. Patients underwent unattended overnight home polysomnography. Ten patients with severe OSAS were revaluated after 6 months of nCPAP therapy. To assess oxidative stress in vivo, we measured urinary 8-iso-PGF2α and serum levels of soluble NOX2-derived peptide (sNOX2-dp). Serum levels of nitrite/nitrate (NOx) were also determined. Flow-mediated brachial artery dilation (FMD) was measured to asses endothelial function.ResultsPatients with severe OSAS had higher urinary 8-iso-PGF2α (p<0.001) and serum NOX2 and lower NOx. A negative association was observed between FMD and OSA severity. Apnea/hypopnea index was significantly correlated with the indices of central obesity and with urinary 8-isoprostanes (r=0.298, p<0.001). The metabolic syndrome (t=-4.63, p<0.001) and urinary 8-isoprostanes (t=-2.02, p<0.05) were the only independent predictors of FMD. After 6-months nCPAP treatment, a significant decrease of serum NOX2, (p<0.005) and urinary 8-iso-PGF2α (p<0.01) was observed, while serum NOx showed only a minor increase. A statistically significant increase of FMD was observed (from 3.6% to 7.0%).ConclusionsThe results of our study indicate that patients with OSAS and cardiometabolic comorbidities have increased oxidative stress and arterial dysfunction that are partially reversed by nCPAP treatment.

Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis.

Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L-carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed.

The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease is an emerging liver disease in Western countries and the most frequent cause of incidental elevation of serum liver enzymes. Dyslipidaemia is frequently observed in patients with non-alcoholic fatty liver disease, and treatment of dyslipidaemia plays a critical role in the overall management of these patients. Moreover, coronary artery disease remains the most common cause of death. Statins are effective lipid-lowering agents, associated with a lowering the risk of cardiovascular events in several interventional randomized clinical trials. However, statins are often underused in patients with non-alcoholic fatty liver disease and many physicians are concerned about the prescription of statins to patients with unexplained persistent elevation of liver enzymes or active liver disease. Based on currently available data, statin therapy, at low-to-moderate doses, seems to be safe and has low liver toxicity. Treatment of dyslipidaemia in patients with non-alcoholic fatty liver disease is recommended and may also improve liver function tests. In these patients, the risks of not taking statins could outweigh the risks of taking the drug. Conversely, the usefulness of statins for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis is still a matter of debate and randomized clinical trials of adequate size and duration are required.

Obesity and Hypercholesterolemia are Associated with NOX2 Generated Oxidative Stress and Arterial Dysfunction

OBJECTIVE To analyze the interplay among oxidative stress, NOX2, the catalytic core of nicotinamide-adenine dinucleotide phosphate oxidase, and endothelial dysfunction in children with obesity and/or hypercholesterolemia. STUDY DESIGN We performed a cross-sectional study comparing flow-mediated arterial dilation (FMD), oxidized low-density lipoprotein, and urinary excretion of isoprostanes (8-iso-PGF2α), as markers of oxidative stress, and NOX2 activity, as assessed by blood levels of soluble NOX2-dp (sNOX2-dp), in a population of 100 children, matched for age and sex, including 40 healthy subjects (HS), 20 children with hypercholesterolemia (HC), 20 obese children (OC), and 20 children with coexistence of hypercholesterolemia and obesity (HOC). RESULTS HOC had higher sNOX2-dp and oxidized low-density lipoprotein levels compared with HS, HC, and OC. HC, OC, and HOC had lower FMD values compared with HS. Urinary 8-iso-PGF2α excretion was higher in HOC compared with HS. FMD was inversely correlated with sNOX2-dp levels (r = -0.483; P < .001) and with the number of cardiovascular risk factors (r = -0.617; P < .001). Multiple linear regression analysis showed that the number of cardiovascular risk factors was the only independent predictive variable associated with FMD (β: -0.585; P < .001; R(2) = 35%) and sNOX2-dp (β: 0.587; P < .001; R(2) = 34%). CONCLUSION The study suggests that NOX2-generating oxidative stress may have a pathogenic role in the functional changes of the arterial wall occurring in HOC.

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

BackgroundChronic 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.MethodsThe 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.ResultsPatients 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.ConclusionsWe 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.

Modern approach to the clinical management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common and emerging form of chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to steatohepatitis, which may progress to cirrhosis, liver cancer, and liver mortality. Common metabolic diseases, which are well established cardiovascular risk factors, have been associated to NAFLD and cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. The pathogenesis of NAFLD appears multifactorial and many mechanisms have been proposed as possible causes of fatty liver infiltration. Management of fatty liver has become a major challenge to healthcare systems as the consequence of the increasing rates of obesity worldwide. First-line management focuses on lifestyle modifications. Moderate weight reduction either by dietary restriction or by increased habitual physical activity is safe and highly recommended. Several therapeutic interventions have been proposed. These include insulin sensitizer agents, lipid lowering drugs, antioxidants such as vitamin E and supplementation of vitamin D3. However, therapeutic strategies have been largely empirical so far, and experimental trials have mostly been carried out in uncontrolled settings with small sample sizes. Metabolic conditions such as diabetes mellitus, obesity, hypertension and hyperlipidemia, should be strongly considered and a multidisciplinary approach should be personalized for individual patients. Treatment of co-morbidities should be regarded as of paramount importance in the management of these patients. The purpose of this review is to examine different approaches for the clinical management of non-alcoholic fatty liver disease.

Reduced Lysosomal Acid Lipase Activity in Adult Patients With Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is characterized by intra-hepatic fat accumulation and mechanisms involved in its pathogenesis are not fully explained. Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism. We investigated its activity in patients with fatty liver. LAL activity (nmol/spot/h) was measured in 100 adult healthy subjects (HS) and in 240 NAFLD patients. A sub-analysis on 35 patients with biopsy-proven non-alcoholic steatohepatitis (NASH) was performed. Median LAL activity was 1.15 (0.95–1.72) in HS. It was significantly reduced in NAFLD [0.78 (0.61–1.01), p < 0.001 vs. HS]. A further reduction was observed in the subgroup of NASH [0.67 (0.51–0.77), p < 0.001 vs. HS]. Patients with LAL activity below median had higher values of serum total cholesterol (p < 0.05) and LDL-c (p < 0.05), and increased serum liver enzymes (ALT, p < 0.001; AST, p < 0.01; GGT, p < 0.01). At multivariable logistic regression analysis, factors associated with LAL activity below median were ALT (OR: 1.018, 95% CI 1.004–1.032, p = 0.011) and metabolic syndrome (OR: 2.551, 95% CI 1.241–5.245, p = 0.011), whilst statin use predicted a better LAL function (OR: 0.464, 95% CI 0.248–0.866, p = 0.016). Our findings suggest a strong association between impaired LAL activity and NAFLD. A better knowledge of the role of LAL may provide new insights in NAFLD pathogenesis.

Non-alcoholic fatty liver disease and cardiovascular disease: epidemiological, clinical and pathophysiological evidences

Non-alcoholic fatty liver disease is recognized as the most common and emerging chronic liver disease in western countries. The disease has been traditionally interpreted as a possibly progressing condition to liver fibrosis and cirrhosis. However, recently, a large number of publications have demonstrated that people with non-alcoholic fatty liver have an increased chance of developing cardiovascular diseases, which represent the major causes of death in this setting. This association is mainly explained by the atherogenic profile of the metabolic syndrome a condition frequently associated with fatty liver, which may represent its hepatic component. Some studies have also shown an association independent of traditional risk factors or of the clinical features of the metabolic syndrome. In this setting, cardiovascular disease seems to be the consequence of low-grade chronic inflammation and increased oxidative stress. Most studies did not differentiate cardiovascular risk between simple steatosis and non-alcoholic steatohepatitis, although the latter seems to be at higher cardiovascular risk. Few studies have investigated the direct correlation between hepatic inflammation and atherosclerosis. Genetic studies will probably improve the interpretation of the increased cardiovascular risk in patients with fatty liver and no metabolic syndrome.

Non-alcoholic fatty liver disease, metabolic syndrome and patatin-like phospholipase domain-containing protein3 gene variants.

BACKGROUND & AIMS Non-alcoholic fatty liver disease was traditionally interpreted as a condition which may progress to liver-related complications. However, the increased mortality is primarily a result of cardiovascular diseases. It has been suggested that fatty liver can be considered as the hepatic consequence of the metabolic syndrome. The aim was to describe the different clinical presentations of non-alcoholic fatty liver disease on the basis of the patatin-like phospholipase domain-containing protein3 (PNPLA3) rs738409 gene variant. METHODS Fatty liver was defined by ultrasonographic Hamaguchis criteria in 211 consecutive subjects with non-alcoholic fatty liver disease. The rs738409 polymorphism was determined by TaqMan assays. Metabolic syndrome was defined according to ATPIII modified criteria. RESULTS Prevalence of PNPLA3-148II, PNPLA3-148IM, and PNPLA3-148MM genotypes was 45.0%, 40.7%, and 14.3% respectively. Prevalence of metabolic syndrome progressively increased with the severity of liver steatosis (from 52.5% to 65.2%, and 82.3% respectively, p<0.01). The PNPLA3-148MM group had significantly lower mean serum triglycerides (p<0.001), Framingham cardiovascular risk score (p<0.01) and lower prevalence of metabolic syndrome (p<0.05) and its components. Age and HOMA-IR were positive independent predictors of metabolic syndrome, while a negative independent association was found between metabolic syndrome and the homozygotes PNPLA3 I148M variant. CONCLUSIONS We suggest a lower prevalence of MetS and reduced cardiovascular risk in NAFLD patients with PNPLA3MM genotype.

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.