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Sant'Ambrogio di Torino, Italy

Musso G.,Gradenigo Hospital | Gambino R.,University of Turin | Cassader M.,University of Turin | Pagano G.,University of Turin
Annals of Medicine | Year: 2011

Background. NAFLD ranges from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH). The natural history of NAFLD and the optimal strategy to identify subjects with progressive liver disease are unclear. Objectives. To assess the evidence in: (1) natural history of NAFLD; and (2) non-invasive methods to differentiate NAFLD histological subtypes. Design and setting. Among 4185 articles published on MEDLINE, Cochrane Library, EMBASE, Pubmed, national and International meeting abstracts through July 2010, 40 articles assessing the natural history of NAFLD and 32 articles evaluating the diagnostic accuracy of non-invasive tests against liver biopsy (LB) were included. Measurements. Two reviewers retrieved articles and evaluated study quality by appropriate scores. Main outcomes were pooled using random-or fixed-effects models. Results. NAFLD has an increased overall mortality (OR: 1.57, 95% CI: 1.182.10), deriving from liver-related and cardiovascular disease, and a 2-fold risk of diabetes. Compared to SS, NASH has a higher liver-related (OR for NASH: 5.71, 2.3114.13; OR for NASH with advanced fibrosis: 10.06, 4.3523.25), but not cardiovascular mortality (OR: 0.91, 0.421.98). Three non-invasive methods received independent validation: pooled AUROC, sensitivity and specificity of cytokeratin-18 for NASH are 0.82 (0.780.88), 0.78 (0.640.92), 0.87 (0.770.98). For NASH with advanced fibrosis, pooled AUROC, sensitivity and specificity of NAFLD fibrosis score and Fibroscan are 0.85 (0.800.93), 0.90 (0.820.99), 0.97 (0.940.99) and 0.94 (0.900.99), 0.94 (0.880.99) and 0.95 (0.890.99). Conclusions. NAFLD warrants screening for cardio-metabolic risk and for progressive liver disease. The combination of three noninvasive tests with LB may optimally individuate patients with NASH, with or without advanced fibrosis. © 2011 Informa UK, Ltd.

Musso G.,Gradenigo Hospital | Gambino R.,University of Turin | Cassader M.,University of Turin
Annual Review of Medicine | Year: 2010

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, viral infection, or other specific causes of liver disease. Currently the most common chronic liver disease, affecting 30% of the Western world, NAFLD may progress to cirrhosis and end-stage liver disease and may increase the risk of developing diabetes and cardiovascular disease. Although its pathogenesis is unclear, NAFLD is tightly associated with insulin resistance and the metabolic syndrome. No established treatment exists, and current research is targeting new molecular mechanisms that underlie NAFLD and associated cardiometabolic disorders. This review discusses some of these emerging molecular mechanisms and their therapeutic implications for the treatment of NAFLD: microRNAs, incretin analogs/antagonists, liver-specific thyromimetics, AMP-activated protein kinase activators, and nuclear receptors farnesoid X receptor and pregane X receptor. © 2010 by Annual Reviews All rights reserved.

Musso G.,Gradenigo Hospital | Gambino R.,University of Turin | Cassader M.,University of Turin
Current Opinion in Lipidology | Year: 2010

Purpose of review: To examine the role of gut microbiota in the regulation of host energy homeostasis and its role in the pathogenesis of obesity, diabetes and nonalcoholic fatty liver disease (NAFLD) Recent findings: Experimental models highlight several mechanisms connecting gut microbiota to host energy metabolism: increased energy harvesting from the diet, regulation of appetite through gut peptide, secretion, regulation of tissue-free fatty acid composition and uptake, storage and oxidation, modulation of intestinal barrier by glucagon-like peptide-2 secretion, activation of innate immunity and hepatic fibrogenesis through the lipopolysaccharide (LPS)-toll-like receptor-4 axis.Gut microbiota manipulation through antibiotics, prebiotics and probiotics yields encouraging results for the treatment of obesity, diabetes and NAFLD in animal models, but data in humans are currently scarce. Summary: Gut microbiota manipulation yielded encouraging results for the treatment of different metabolic disorders in experimental models. However, changing intestinal microbiota may be more difficult in free-living individuals compared to standardized laboratory models, and its long-term consequences are unknown. To safely and effectively change human gut microflora, future research should highlight the complex hormonal, immunomodulatory and metabolic mechanisms underlying microbiota-host interactions in different tissues and candidate treatments should be evaluated in well designed trials with patient-oriented end-points. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Musso G.,Gradenigo Hospital | Gambino R.,University of Turin | Cassader M.,University of Turin
Diabetes Care | Year: 2010

The connection between gut microbiota and energy homeostasis and inflammation and its role in the pathogenesis of obesity-related disorders are increasingly recognized. Animals models of obesity connect an altered microbiota composition to the development of obesity, insulin resistance, and diabetes in the host through several mechanisms: increased energy harvest from the diet, altered fatty acid metabolism and composition in adipose tissue and liver, modulation of gut peptide YY and glucagon-like peptide (GLP)-1 secretion, activation of the lipopolysaccharide toll-like receptor-4 axis, and modulation of intestinal barrier integrity by GLP-2. Instrumental for gut microbiota manipulation is the understanding of mechanisms regulating gut microbiota composition. Several factors shape the gut microflora during infancy: mode of delivery, type of infant feeding, hospitalization, and prematurity. Furthermore, the key importance of antibiotic use and dietary nutrient composition are increasingly recognized. The role of the Western diet in promoting an obesogenic gut microbiota is being confirmation in subjects. Following encouraging results in animals, several short-term randomized controlled trials showed the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance. Future research is needed to unravel the hormonal, immunomodulatory, and metabolic mechanisms underlying microbe-microbe and microbiota-host interactions and the specific genes that determine the health benefit derived from probiotics. While awaiting further randomized trials assessing long-term safety and benefits on clinical end points, a healthy lifestyle - including breast lactation, appropriate antibiotic use, and the avoidance of excessive dietary fat intake - may ensure a friendly gut microbiota and positively affect prevention and treatment of metabolic disorders. © 2010 by the American Diabetes Association.

Musso G.,Gradenigo Hospital | Gambino R.,University of Turin | Cassader M.,University of Turin | Pagano G.,University of Turin
Hepatology | Year: 2010

Nonalcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). NAFLD carries a higher risk of cardio-metabolic and liver-related complications, the latter being confined to NASH and demanding specific treatment. We assessed the efficacy of proposed treatments for NAFLD/NASH by reviewing reports of randomized controlled trials (RCTs) on online databases and national and international meeting abstracts through January 2010. Primary outcome measure was histological improvement; secondary outcome was biochemical improvement; improvement in radiological steatosis was also evaluated. Two reviewers extracted articles using predefined quality indicators, independently and in duplicate. Main outcomes of randomized controlled trials (RCTs) were pooled using random-effects or fixed-effects models. Publication bias was assessed by funnel plots. Forty-nine RCTs (30 in NASH) were included: 23 RCTs (22 in NASH, 1 in NAFLD) had post-treatment histology. Most RCTs were small and did not exceed 1-year duration. Weight loss, thiazolidinediones (especially pioglitazone), and antioxidants were most extensively evaluated. Weight loss was safe and dose-dependently improved histological disease activity in NASH, but more than 50% of patients failed to achieve target weight loss. Thiazolidinediones improved steatosis and inflammation but yielded significant weight gain. RCTs with antioxidants yielded conflicting results and were heterogeneous with respect to type and dose of drug, duration, implementation of lifestyle intervention. Among the other agents, pentoxifylline, telmisartan and L-carnitine improved liver histology in at least 1 RCT in NASH; polyunsaturated fatty acid (PUFA) ameliorated biochemical and radiological markers of NAFLD. Other approaches yielded negative results. Conclusion: Well-designed RCTs of adequate size and duration, with histological endpoints, are needed to assess long-term safety and efficacy of proposed treatments on patient-oriented clinical outcomes. Copyright © 2010 by the American Association for the Study of Liver Diseases.

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