Maurizio Cassader

Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.

Abstract 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: 1.18–2.10), 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, 2.31–14.13; OR for NASH with advanced fibrosis: 10.06, 4.35–23.25), but not cardiovascular mortality (OR: 0.91, 0.42–1.98). Three non-invasive methods received independent validation: pooled AUROC, sensitivity and specificity of cytokeratin-18 for NASH are 0.82 (0.78–0.88), 0.78 (0.64–0.92), 0.87 (0.77–0.98). For NASH with advanced fibrosis, pooled AUROC, sensitivity and specificity of NAFLD fibrosis score and Fibroscan are 0.85 (0.80–0.93), 0.90 (0.82–0.99), 0.97 (0.94–0.99) and 0.94 (0.90–0.99), 0.94 (0.88–0.99) and 0.95 (0.89–0.99). 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.

Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and is considered the hepatic manifestation of metabolic syndrome. The hallmark of NAFLD is hepatic neutral lipid accumulation, mainly triacylglycerol, in the absence of significant ethanol consumption, viral infection or other specific etiologies. Hepatic lipid accumulation results from an imbalance between lipid availability (from circulating lipid uptake or de novo lipogenesis) and lipid disposal (via free fatty acid oxidation or triglyceride-rich lipoprotein secretion) and eventually triggers lipoperoxidative stress and hepatic injury. Each of these steps is altered in NAFLD, although to a different extent. Regulation of these pathways is complex and involves nuclear receptors, membrane transport proteins and cellular enzymes. We will review available data on different steps of hepatic lipid metabolism in NAFLD and recent advances in understanding molecular mechanisms underlying hepatic fat accumulation in these subjects.

Obesity, Diabetes, and Gut Microbiota: The hygiene hypothesis expanded?

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.

Interactions Between Gut Microbiota and Host Metabolism Predisposing to Obesity and Diabetes

Novel, culture-independent, molecular and metagenomic techniques have provided new insight into the complex interactions between the mammalian host and gut microbial species. It is increasingly evident that gut microbes may shape the host metabolic and immune network activity and ultimately influence the development of obesity and diabetes. We discuss the evidence connecting gut microflora to obesity and to type 1 and type 2 diabetes, and we present recent insights into potential mechanisms underlying this relationship: increased nutrient absorption from the diet, prolonged intestinal transit time, altered bile acid entero-hepatic cycle, increased cellular uptake of circulating triglycerides, enhanced de novo lipogenesis, reduced free fatty acid oxidation, altered tissue composition of biologically active polyunsaturated fatty acid, chronic low-grade inflammation triggered by the endotoxin toll-like receptor 4 axis, and altered intestinal barrier function.

Adipokines in NASH: Postprandial lipid metabolism as a link between adiponectin and liver disease†

Circulating levels of four adipokines (adiponectin, TNF‐α, leptin, and resistin) and the postprandial lipid and adiponectin responses to an oral fat load were assessed in 25 non‐obese, non‐diabetic patients with biopsy‐proven nonalcoholic steatohepatitis (NASH) and correlated with metabolic indices and liver histology. Circulating adiponectin was lower in NASH compared with controls (5,476 ± 344 vs. 11,548 ± 836 ng/mL; P = .00001) and on multiple regression analysis correlated negatively with liver steatosis, necroinflammation (OR = 5.0; P = .009), and fibrosis (OR = 8.0; P = .003).The magnitude of postprandial lipemia was significantly higher in NASH than in controls and was related to fasting adiponectin (β = −0.78; P = .00003). Controls showed a significant increase in serum adiponectin in response to the fat load, whereas patients with NASH showed a slight decrease. Postprandial free fatty acids response correlated inversely with adiponectin response in both groups and independently predicted the severity of liver steatosis in NASH (β = 0.51; P = .031). In conclusion, hypoadiponectinemia is present before overt diabetes and obesity appear and correlates with the severity of liver histology in NASH. Impaired postprandial lipid metabolism may be an additional mechanism linking hypoadiponectinemia and NASH and posing a higher cardiovascular risk to these subjects. The mechanism(s) underlying these differences are unknown, but the type of dietary fat seems to play a role. These findings may have important pathogenetic and therapeutic implications in both liver and metabolic disease. (HEPATOLOGY 2005.)

Hypoadiponectinemia Predicts the Severity of Hepatic Fibrosis and Pancreatic Beta-Cell Dysfunction in Nondiabetic Nonobese Patients with Nonalcoholic Steatohepatitis

OBJECTIVES:The relationships between the adipokines tumor necrosis factor (TNF)-α and adiponectin and the parameters of glucose homeostasis and severity of liver disease were assessed in nonobese nondiabetic subjects with nonalcoholic steatohepatitis (NASH).METHODS:A frequently sampled intravenous glucose tolerance test, serum cytokine measurement, and 7-day alimentary record were performed in 20 biopsy-proven NASH patients and 45 age-, sex-, and BMI-matched controls (30 insulin sensitive and 15 insulin resistant).RESULTS:Patients with NASH had impaired pancreatic β-cell function compared with both insulin-sensitive (adaptation index, AI: 97.7 ± 17.7 vs 307.4 ± 24.1 min−2 mmol−1 L; p = 0.00001) and insulin-resistant (adaptation index, AI: 97.7 ± 17.7 vs 201.4 ± 41.1 min−2 mmol−1 L; p = 0.001) controls. Serum adiponectin levels were also significantly lower in the NASH group than in the two control groups and correlated with adaptation index and with the severity of hepatic steatosis, necroinflammation, and fibrosis. When NASH patients were grouped according to the severity of histological liver damage, adiponectin was the only variable discriminating patients with higher necroinflammatory grade and fibrosis score from those with milder lesions.CONCLUSIONS:β-cell secretory impairment is present in nonobese patients with NASH before glucose intolerance appears and may contribute to their increased risk for developing diabetes. Hypoadiponectinemia is a feature of NASH and may have a pathogenetic role in β-cell dysfunction and in hepatic necroinflammation and fibrosis, independently of insulin resistance, visceral fat accumulation, TNF-α axis activity, and dietary habits. Our findings provide further rationale for therapeutic approaches aimed at increasing adiponectin levels together with restoring β-cell function and insulin sensitivity.

A novel approach to control hyperglycemia in type 2 diabetes: Sodium glucose co-transport (SGLT) inhibitors. Systematic review and meta-analysis of randomized trials

Abstract Background. Current treatment of hyperglycemia in type 2 diabetes (T2DM) is often ineffective and has unwanted effects. Therefore, novel antidiabetic drugs are under development. Objective. To assess efficacy and safety of the new antidiabetic drugs sodium glucose co-transport-2 (SGLT2) inhibitors in T2DM. Design and setting. Among 151 articles published on MEDLINE, Cochrane Library, EMBASE, PubMed, International meeting abstracts through December 2010, 13 randomized placebo-controlled trials (RCT) 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. Dapagliflozin significantly reduced HbA1c (weighted mean difference (WMD) −0.52%; 95% CI −0.46, −0.57%; P < 0.00001) fasting plasma glucose (WMD −18.28 mg/dL; 95% CI −20.66, −15.89; P < 0.00001), body mass index (WMD −1.17%; −1.41, −0.92%; P < 0.00001), systolic (WMD −4.08 mmHg; −4.91, −3.24), and diastolic (WMD −1.16 mmHg; −1.67, −0.66) blood pressure, and serum uric acid (WMD −41.50 μmol/L; −47.22, −35.79). Other SGLT2 inhibitors showed similar results. Dapagliflozin treatment increased the risk of urinary (OR 1.34; 1.05–1.71) and genital (OR 3.57; 2.59–4.93) tract infection; it also mildly increased the risk of hypoglycemia (OR 1.27; 1.05–1.53) when co-administered with insulin. Limitations. Limitations of the literature include the small number, size, and duration of RCTs. Conclusions. Pending confirmation from larger RCTs, this analysis shows SGLT2 inhibitors are safe and effective for hyperglycemia treatment in T2DM.

Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis

Emerging experimental and human evidence has linked altered hepatic cholesterol homeostasis and free cholesterol (FC) accumulation to the pathogenesis of non-alcoholic steatohepatits (NASH). This review focuses on cellular mechanisms of cholesterol toxicity involved in liver injury and on alterations in cholesterol homeostasis promoting hepatic cholesterol overload in NASH. FC accumulation injures hepatocytes directly, by disrupting mitochondrial and endoplasmic reticulum (ER) membrane integrity, triggering mitochondrial oxidative injury and ER stress, and by promoting generation of toxic oxysterols, and indirectly, by inducing adipose tissue dysfunction. Accumulation of oxidized LDL particles may also activate Kupffer and hepatic stellate cells, promoting liver inflammation and fibrogenesis. Hepatic cholesterol accumulation is driven by a deeply deranged cellular cholesterol homeostasis, characterized by elevated cholesterol synthesis and uptake from circulating lipoproteins and by a reduced cholesterol excretion. Extensive dysregulation of cellular cholesterol homeostasis by nuclear transcription factors sterol regulatory binding protein (SREBP)-2, liver X-receptor (LXR)-α and farnesoid X receptor (FXR) plays a key role in hepatic cholesterol accumulation in NASH. The therapeutic implications and opportunities for normalizing cellular cholesterol homeostasis in these patients are also discussed.

Should Nonalcoholic Fatty Liver Disease Be Included in the Definition of Metabolic Syndrome? A cross-sectional comparison with Adult Treatment Panel III criteria in nonobese nondiabetic subjects

OBJECTIVE—The ability of the Adult Treatment Panel III (ATP III) criteria of metabolic syndrome to identify insulin-resistant subjects at increased cardiovascular risk is suboptimal, especially in the absence of obesity and diabetes. Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and is emerging as an independent cardiovascular risk factor. We compared the strength of the associations of ATP III criteria and of NAFLD to insulin resistance, oxidative stress, and endothelial dysfunction in nonobese nondiabetic subjects. RESEARCH DESIGN AND METHODS—Homeostasis model assessment of insulin resistance (HOMA-IR) >2, oxidative stress (nitrotyrosine), soluble adhesion molecules (intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), and circulating adipokines (tumor necrosis factor-α, leptin, adiponectin, and resistin) were cross-sectionally correlated to ATP III criteria and to NAFLD in 197 unselected nonobese nondiabetic subjects. RESULTS—NAFLD more accurately predicted insulin resistance than ATP III criteria: sensitivity 73 vs. 38% (P = 0.0001); positive predictive value: 81 vs. 62% (P = 0.035); negative predictive value 87 vs. 74% (P = 0.012); positive likelihood ratio 4.39 vs. 1.64 (P = 0.0001); and negative likelihood ratio 0.14 vs. 0.35 (P = 0.0001). Adding NAFLD to ATP III criteria significantly improved their diagnostic accuracy for insulin resistance. Furthermore, NAFLD independently predicted HOMA-IR, nitrotyrosine, and soluble adhesion molecules on logistic regression analysis; the presence of NAFLD entailed more severe oxidative stress and endothelial dysfunction, independent of adiposity or any feature of the metabolic syndrome in insulin-resistant subjects. CONCLUSIONS—NAFLD is more tightly associated with insulin resistance and with markers of oxidative stress and endothelial dysfunction than with ATP III criteria in nonobese nondiabetic subjects and may help identify individuals with increased cardiometabolic risk in this population.

Non-alcoholic fatty liver disease from pathogenesis to management: an update.

Non‐alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the Western world, is tightly associated with obesity and metabolic syndrome. NAFLD entails an increased cardiometabolic and liver‐related risk, the latter regarding almost exclusively non‐alcoholic steatohepatitis (NASH), the progressive form of NAFLD. Pathogenetic models encompass altered hepatic lipid partitioning and adipokine action, increased oxidative stress, free fatty acid lipotoxicity. On this basis, lifestyle‐, drug‐ or surgically induced weight loss, insulin sensitizers, antioxidants, lipid‐lowering drugs have been evaluated in NAFLD/NASH. Most trials are small, of short duration, nonrandomized, without histological end points, thus limiting assessment of long‐term safety and efficacy of proposed treatments.