Francesco Angelico

Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes

BackgroundHypovitaminosis D has been recently recognized as a worldwide epidemic. Since vitamin D exerts significant metabolic activities, comprising free fatty acids (FFA) flux regulation from the periphery to the liver, its deficiency may promote fat deposition into the hepatocytes. Aim of our study was to test the hypothesis of a direct association between hypovitaminosis D and the presence of NAFLD in subjects with various degree of insulin-resistance and related metabolic disorders.MethodsWe studied 262 consecutive subjects referred to the Diabetes and Metabolic Diseases clinics for metabolic evaluation. NAFLD (non-alcoholic fatty liver disease) was diagnosed by upper abdomen ultrasonography, metabolic syndrome was identified according to the Third Report of National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATPIII) modified criteria. Insulin-resistance was evaluated by means of HOMA-IR. Fatty-Liver-Index, a recently identified correlate of NAFLD, was also estimated. Serum 25(OH)vitamin D was measured by colorimetric method.ResultsPatients with NAFLD (n = 162,61.8%) had reduced serum 25(OH) vitamin D levels compared to subjects without NAFLD (14.8 ± 9.2 vs 20.5 ± 9.7 ng/ml, p < 0.001, OR 0.95, IC 95% 0.92-0.98). The relationship between NAFLD and reduced 25(OH)vitamin D levels was independent from age, sex, triglycerides, high density lipoproteins (HDL) and glycaemia (p < 0.005) and Fatty Liver Index inversely correlated with low 25(OH) vitamin D regardless sex, age and HOMA-IR (p < 0.007).ConclusionsLow 25(OH)vitamin D levels are associated with the presence of NAFLD independently from metabolic syndrome, diabetes and insulin-resistance profile.

Non-alcoholic fatty liver syndrome: A hepatic consequence of common metabolic diseases

Background and Aims: The association of liver steatosis with a number of common metabolic conditions has been suggested. The aim of the present study was to evaluate the clinical features of subjects with different severities of steatosis.

Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus

Evidence suggests an association between low serum 25‐hydroxy‐vitamin D3 [25(OH)D3] levels and the presence and prognosis of liver disease. Vitamin D receptor (VDR) has been widely detected in the liver, but its expression in the course of liver disease has never been investigated. We evaluated the hepatic expression of VDR along with that of vitamin D 25‐hydroxylases in patients with nonalcoholic steatohepatitis (NASH) or chronic hepatitis C (CHC) and its relationship with hepatic histological features and serum 25(OH)D3 levels. We evaluated 61 patients (25 NASH and 36 CHC) who had undergone liver biopsy for clinical purposes and 20 subjects without liver disease. Serum 25(OH)D3 was measured via colorimetric assay. Expression of VDR, CYP2R1, and CYP27A1 was evaluated via immunohistochemistry in hepatocytes, cholangiocytes, and liver inflammatory cells. Parenchymal and inflammatory cells from liver biopsies of patients with NASH and CHC expressed VDR, CYP2R1, and CYP27A1. In NASH patients, VDR expression on cholangiocytes was inversely correlated with steatosis severity (P < 0.02), lobular inflammation (P < 0.01), and nonalcoholic fatty liver disease score (P < 0.03). Moreover, expression of CYP2R1 in hepatocytes correlated strongly with VDR positivity on liver inflammatory cells. In CHC subjects, fibrosis stage was associated with low hepatic CYP27A1 expression, whereas portal inflammation was significantly higher in patients with VDR‐negative inflammatory cells (P < 0.009) and low VDR expression in hepatocytes (P < 0.03). Conclusion: VDR is widely expressed in the liver and inflammatory cells of chronic liver disease patients and its expression is negatively associated with the severity of liver histology in both NASH and CHC patients. These data suggest that vitamin D/VDR system may play a role in the progression of metabolic and viral chronic liver damage. (HEPATOLOGY 2012;56:2180–2187)

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.

Reduced Atherosclerotic Burden in Subjects With Genetically Determined Low Oxidative Stress

Objective—NADPH oxidase, one of the most important enzymes producing reactive oxidant species, is suggested to play a role in experimental atherosclerosis, but its role in human atherosclerosis is still unclear. We hypothesized that a reduced activity of NADPH oxidase might be linked to a reduced atherosclerotic burden. Methods and Results—Thirty-one women carriers of hereditary deficiency of NOX2, the catalytic subunit of NADPH oxidase, were matched for sex and age with 31 controls and 31 obese women. Flow-mediated dilation and intima-media thickness, 2 surrogate markers of atherosclerosis, serum activity of NOX2, urinary isoprostanes, serum levels of nitrite/nitrate, and platelet production of isoprostanes and nitrite/nitrate were determined. Compared with controls (5.7±3.0% and 0.60±0.11 mm), carriers of NOX2 deficiency had higher flow-mediated dilation (9.2±5.0%; P<0.001) and lower intima-media thickness (0.50±0.11 mm; P=0.002), whereas obese women had lower flow-mediated dilation (3.2±2.1%; P=0.007) and higher intima-media thickness (0.71±0.15 mm; P<0.001). Compared with controls, carriers of NOX2 deficiency had lower urinary isoprostanes (132.6±87.3 versus 82.3±46.0 pg/mg creatinine; P=0.007) and serum NOX2 activity (24.9±19.3 versus 12.8±11.9 pg/mL; P=0.004) and higher serum nitrite/nitrate (23.8±7.6 versus 30.5±6.3 µmol/L; P<0.001), whereas obese women had higher urinary isoprostanes (132.6±87.3 versus 182.2±84.6 pg/mg creatinine; P=0.008) and serum NOX2 activity (24.9±19.3 versus 36.1±18.6 pg/mL; P=0.008) and lower serum nitrite/nitrate (23.8±7.6 versus 12.6±4.2 µmol/L; P<0.001). Flow-mediated dilation correlated with intima-media thickness (r=–0.433; P<0.001), serum NOX2 activity (r=–325; P<0.001), and urinary isoprostanes (r=–0.314; P=0.002). Ex vivo study showed that, compared with controls, platelets from carriers of NOX2 deficiency had lower isoprostanes (P<0.001) and higher nitrite/nitrate (P<0.001), whereas platelets from obese women had higher isoprostanes (P<0.001) and lower nitrite/nitrate (P=0.013). Conclusion—The study shows reduced atherosclerotic burden in carriers of NOX2 deficiency, suggesting that oxidative stress generated by this enzymatic pathway is implicated in human atherosclerosis.

Incidence of Myocardial Infarction and Vascular Death in Elderly Patients With Atrial Fibrillation Taking Anticoagulants: Relation to Atherosclerotic Risk Factors

BACKGROUND Recent findings suggest that patients with atrial fibrillation (AF), in addition being at thromboembolic risk, are at risk of myocardial infarction (MI). Our aim was to investigate predictors of MI and cardiovascular death in a cohort of patients with AF who were taking anticoagulants. METHODS We prospectively followed up 1,019 patients with AF for a median of 33.7 months (3,223 person-years). All patients were treated with oral vitamin K antagonists. Primary outcome was a composite end point of cardiovascular events (CVEs) including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death. RESULTS The mean age of the patients was 73.2 years, and 43.8% were women. At follow-up, 111 CVEs (3.43%/y) had occurred: 47 fatal-nonfatal MI/revascularization and 64 cardiovascular deaths. In addition, 31 stroke/transient ischemic attacks (0.96%/y) were recorded. Patients experiencing CVEs were older (P < .001) and had a higher prevalence of metabolic syndrome (MetS) (P = .005), heart failure (P = .001), and prior cardiac (P < .001) and cerebrovascular events (P < .001). On a Cox proportional hazard analysis, age (hazard ratio [HR], 1.083; 95% CI, 1.053-1.113; P < .001), smoking (HR, 2.158; 95% CI, 1.193-3.901; P = .011), history of cerebrovascular (HR, 1.704; 95% CI, 1.119-2.597; P = .013) and cardiac (HR, 1.658; 95% CI, 1.105-2.489; P = .015) events, MetS (HR, 1.663; 95% CI, 1.107-2.499; P = .014), heart failure (HR, 1.584; 95% CI, 1.021-2.456; P = .040), and male sex (HR, 1.499; 95% CI, 1.010-2.223; P = .044) predicted CVEs. CONCLUSIONS Patients with AF still experience a high rate of CVEs despite receiving anticoagulant treatment. MetS is a common clinical feature in patients with AF, which increases the risk of CVEs. A holistic approach is needed to reduce the cardiovascular risk in patients with AF. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01882114; URL: www.clinicaltrials.gov.

Obstructive sleep apnoea syndrome and the metabolic syndrome in an internal medicine setting

BACKGROUND Obstructive sleep apnoea syndrome (OSAS) is widely accepted as a cardiovascular risk factor. Lately it has been considered in turn as both a component and one of the causes of the metabolic syndrome (MS). METHODS We studied 281 heavy snorers of both sexes consecutively attending a metabolic clinic. Aim was to evaluate the association of OSAS and MS in a large series of patients within an internal medicine setting. Patients underwent a clinical and biochemical work up and performed unattended polysomnography. RESULTS Of 226 non-diabetic snorers, 48 had primary snoring; 54 mild, 51 moderate, and 73 severe OSAS. A positive association was found between OSAS severity, central obesity indices and the mean metabolic score (p=0.016). Prevalence of hypertension increased with OSA severity (p=0.010). Polysomnographic indices were correlated with the metabolic score, insulin levels and central obesity indices. At regression analysis, male sex (t=3.92; p=0.000) and waist circumference (t=3.93; p=0.000) were independently associated with AHI (apnoea/hypopnoea index), while ODI (oxygen desaturation index) and waist circumference were the independent predictors (t=2.16; p=0.033 and t=3.74; p=0.000 respectively) of the metabolic score. Prevalence of OSA was 83% in 55 patients with diabetes and 34% had severe OSA. Almost all diabetics with OSA had MS. The metabolic score was higher in diabetic OSA as compared to non-diabetic OSAS (p=0.000). CONCLUSIONS Our findings show a high prevalence of OSAS among patients referred to a metabolic outpatient clinic because of suspected metabolic disorders and heavy snoring and suggest a strong bidirectional association between OSAS and MS.