Oxidative stress: new insights on the association of nonalcoholic 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

Phenotypical heterogeneity linked to adipose tissue dysfunction in patients with type 2 diabetes

Adipose tissue (AT) inflammation leads to increased free fatty acid (FFA) efflux and ectopic fat deposition, but whether AT dysfunction drives selective fat accumulation in specific sites remains unknown. The aim of the present study was to investigate the correlation between AT dysfunction, hepatic/pancreatic fat fraction (HFF, PFF) and the associated metabolic phenotype in patients with Type 2 diabetes (T2D). Sixty-five consecutive T2D patients were recruited at the Diabetes Centre of Sapienza University, Rome, Italy. The study population underwent clinical examination and blood sampling for routine biochemistry and calculation of insulin secretion [homoeostasis model assessment of insulin secretion (HOMA-β%)] and insulin-resistance [homoeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (ADIPO-IR)] indexes. Subcutaneous (SAT) and visceral (VAT) AT area, HFF and PFF were determined by magnetic resonance. Some 55.4% of T2D patients had non-alcoholic fatty liver disease (NAFLD); they were significantly younger and more insulin-resistant than non-NAFLD subjects. ADIPO-IR was the main determinant of HFF independently of age, sex, HOMA-IR, VAT, SAT and predicted severe NAFLD with the area under the receiver operating characteristic curve (AUROC)=0.796 (95% confidence interval: 0.65-0.94, P=0.001). PFF was independently associated with increased total adiposity but did not correlate with AT dysfunction, insulin resistance and secretion or NAFLD. The ADIPO-IR index was capable of predicting NAFLD independently of all confounders, whereas it did not seem to be related to intrapancreatic fat deposition; unlike HFF, higher PFF was not associated with relevant alterations in the metabolic profile. In conclusion, the presence and severity of AT dysfunction may drive ectopic fat accumulation towards specific targets, such as VAT and liver, therefore evaluation of AT dysfunction may contribute to the identification of different risk profiles among T2D patients

TEM study of homoepitaxial diamond layers scheduled for high power devices: FIB method of sample preparation

Homoepitaxial diamond structure observation by transmission electron microscopy (TEM) is still a very hard job due to the difficulty in preparing electron transparent samples for the further observation. The present contribution details the experimental operations with their respective conditions step by step. Finally high resolution TEM (HREM) observations of a CVD grown epilayer on a unnintentionally doped HPHT (001) oriented substrate are present to show the high quality of the sample preparation method.4 page

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 prote in vitro nectin (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 steatosi

No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder worldwide, reaching prevalence up to 90 % in obese patients with type 2 diabetes (T2D), and representing an independent risk factor for cardiovascular mortality. Furthermore, the coexistence of T2D and NAFLD leads to higher incidence of diabetes’ complications and additive detrimental liver outcomes. The existence of a close association between NAFLD and hypovitaminosis D, along with the anti-inflammatory and insulin-sensitizing properties of vitamin D, have been largely described, but vitamin D effects on hepatic fat content have never been tested in a randomized controlled trial. We assessed the efficacy and safety of 24-week oral high-dose vitamin D supplementation in T2D patients with NAFLD. Methods: This randomized, double-blind, placebo-controlled trial was carried out at the Diabetes Centre of Sapienza University, Rome, Italy, to assess oral treatment with cholecalciferol (2000 IU/day) or placebo in T2D patients with NAFLD. The primary endpoint was reduction of hepatic fat fraction (HFF) measured by magnetic resonance; as hepatic outcomes, we also investigated changes in serum transaminases, CK18-M30, N-terminal Procollagen III Propeptide (P3NP) levels, and Fatty Liver Index (FLI). Secondary endpoints were improvement in metabolic (fasting glycaemia, HbA1c, lipids, HOMA-IR, HOMA-β, ADIPO-IR, body fat distribution) and cardiovascular (ankle-brachial index, intima-media thickness, flow-mediated dilatation) parameters from baseline to end of treatment. Results: Sixty-five patients were randomized, 26 (cholecalciferol) and 29 (placebo) subjects completed the study. 25(OH) vitamin D significantly increased in the active treated group (48.15 ± 23.7 to 89.80 ± 23.6 nmol/L, P < 0.001); however, no group differences were found in HFF, transaminases, CK18-M30, P3NP levels or FLI after 24 weeks. Vitamin D neither changed the metabolic profile nor the cardiovascular parameters. Conclusions: Oral high-dose vitamin D supplementation over 24 weeks did not improve hepatic steatosis or metabolic/cardiovascular parameters in T2D patients with NAFLD. Studies with a longer intervention period are warranted for exploring the effect of long time exposure to vitamin D

Dietary fat intake as a risk factor for the development of diabetes. Multinational, multicenter study of the Mediterranean Group for the Study of Diabetes (MGDS)

In the context of the Multinational MGSD Nutrition Study, three groups of subjects were studied: 204 subjects with recently diagnosed diabetes(RDM),42subjectswithundiagnoseddiabetes(UDM)(AmericanDiabetesAssociation criteria—fasting plasma glucose [FPG] 126 mg/dl), and 55 subjects with impaired fasting glucose(IFG)(FPG 110and126mg/dl).Eachgroupwascomparedwithacontrolgroupof nondiabetic subjects, matched one by one for center, sex, age, and BMI. Nutritional habits were evaluated by a dietary history method, validated against the 3-day diet diary. In RDM, the questionnaire referred to the nutritional habits before the diagnosis of diabetes. Demographic data were collected, and anthropometrical and biochemical measurements were taken. RESULTS— Compared with control subjects, RDM more frequently had a family history of diabetes(49.0vs.14.2%;P0.001),exercisedless(exerciseindex53.5vs.64.4;P0.01),and more frequently had sedentary professions (47.5 vs. 27.4%; P 0.001). Carbohydrates contributed less to their energy intake (53.5 vs. 55.1%; P 0.05), whereas total fat (30.2 0.5 vs. 27.8 0.5%; P 0.001) and animal fat (12.2 0.3 vs. 10.8 0.3%; P 0.01) contributed moreandtheplant-to-animalfatratiowaslower(1.50.1vs.1.80.1;P0.01).UDMmore frequentlyhadafamilyhistoryofdiabetes(38.1vs.19.0%;P0.05)andsedentaryprofessions (58.5vs.34.1%;P0.05),carbohydratescontributedlesstotheirenergyintake(47.61.7vs. 52.81.4%;P0.05),totalfat(34.71.5vs.30.41.2%;P0.05)andanimalfat(14.2 0.9 vs. 10.6 0.7%; P 0.05) contributed more, and the plant-to-animal fat ratio was lower (1.6 0.2 vs. 2.3 0.4; P 0.05). IFG differed only in the prevalence of family history of diabetes (32.7 vs. 16.4%; P 0.05). CONCLUSIONS— Our data support the view that increased animal fat intake is associated with the presence of diabetes

Challenges in improving adherence to diet and drug treatment in hypercholesterolemia patients

: Poor adherence to chronic disease treatment may seriously compromise the effectiveness of therapy, characterizing itself as a critical element for the population's health, both from the point of view of quality of life and health economics. The causes of low adherence are many and can depend on the patient, the physician and the healthcare system. Low adherence to dietary recommendations and lipid-lowering drug therapy for hypercholesterolemia is a widespread phenomenon that may strongly limit the great advantages of serum lipid reduction strategies in primary and secondary cardiovascular prevention. Many patients discontinue treatment, and adherence decreases with time. Increasing therapeutic adherence can have a much greater impact on the health of the population than any other therapeutic advance. There are numerous strategies to increase therapy adherence according to behavior change theories. They concern the doctor and the patient. Some must be implemented at the time of prescription, others later during the follow-up. The active role of the patient in the therapeutic decision and the shared definition of LDL cholesterol targets are of paramount importance. The aim of this narrative review is to summarize evidence on current levels of adherence to lipid-lowering strategies, the causes of the lack of adequate adherence and possible physician-applicable strategies to improve it

Similar reduction of cholesterol-adjusted Vitamin E serum levels in simple steatosis and non-alcoholic steatohepatitis

OBJECTIVES: Reduced vitamin E levels have been reported in patients with non-alcoholic steatohepatitis (NASH), but no conclusive data on patients with simple steatosis (SS) are available. Aim of this study was to investigate the association betweenserum vitamin E levels and SS. METHODS: A cohort of 312 patients with cardio-metabolic risk factors was screened for liver steatosis by ultrasonography (US). We reasonably classified as SS patients with US-fatty liver, normal liver function tests (LFTs) and with Cytokeratin 18 o246 mIU/ml. Liver biopsy was performed in 41 patients with US-fatty liver and persistent elevation of LFTs (46 months). Serum cholesterol-adjusted vitamin E (Vit E/chol) levels were measured. RESULTS: Mean age was 53.9±12.5 years and 38.4% were women. Non-alcoholic fatty liver disease (NAFLD) was detected at US in 244 patients; of those 39 had biopsy-proven NASH and 2 borderline NASH. Vit E/chol was reduced in both SS (3.4±2.0, Po0.001), and NASH (3.5±2.1, P=0.006) compared with non-NAFLD patients (4.8±2.0 μmol/mmol chol). No difference was found between SS and NASH (P=0.785). After excluding patients with NASH, a multivariable logistic regression analysis found that Vit E/chol (odds ratio (OR): 0.716, 95% confidence interval (CI) 0.602–0.851, Po0.001), alanine aminotransferase (ALT, OR: 1.093, 95% CI 1.029–1.161, P=0.004), body mass index (OR: 1.162, 95% CI 1.055–1.279, P=0.002) and metabolic syndrome (OR: 5.725, 95% CI 2.247–14.591, Po0.001) were factors independently associated with the presence of SS. CONCLUSIONS: Reduced vitamin E serum levels are associated with SS, with a similar reduction between patients with SS and NASH, compared with non-NAFLD patients. Our findings suggest that the potential benefit of vitamin E supplementation should be investigated also in patients with SS

Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer disease

Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America. Known pathogenic mutations were found in 1.05% of the sporadic cases, in 0.69% of the cognitively normal participants and in 4.22% of the families. A trend towards enrichment, albeit non-significant, was observed for most AD, FTD and PD genes. Only PSEN1 and PINK1 showed consistent association with AD cases when we used ExAC as the control population. These results suggest that current study designs may contain heterogeneity and contamination of the control population, and that current statistical methods for the discovery of novel genes with real pathogenic variants in complex late onset diseases may be inadequate or underpowered to identify genes carrying pathogenic mutations