Publications (92)612.44 Total impact
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Article: PNPLA3 I148M affects liver steatosis in patients with chronic hepatitis B.
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ABSTRACT: Steatosis is a common histopathological feature of chronic hepatitis B (CHB), and has been associated with the severity of liver disease. Recently, the rs738409 I148M PNPLA3 polymorphism has been demonstrated to influence steatosis susceptibility and fibrosis progression in patients with different liver disease, but no data are yet available for CHB. Aim of this study was to evaluate whether PNPLA3 I148M influences steatosis susceptibility in a large series of patients with CHB. We enrolled 235 treatment-naïve CHB patients consecutively examined by percutaneous liver biopsy. In ≥ 2 cm long liver tissue cores, steatosis and fibrosis were staged by Kleiner and METAVIR scores, respectively. The I148M polymorphism was determined by Taqman assays. Steatosis was present in 146 (62%) patients, of whom 24 (10%) had severe (>33% of hepatocytes) steatosis. Steatosis was independently associated with age (OR 2.67, CI 1.50-4.92 for age≥50 years), BMI (OR 2.84, CI 1.30-6.76 for BMI≥27.5 Kg/m(2) ), diabetes or impaired fasting glucose (OR 4.45, CI 1.10-30.0), and PNPLA3 148M allele (OR 1.62, CI 1.00-7.0 for each 148M allele). Independent predictors of severe steatosis were BMI (OR 3.60, CI 1.39-9.22 for BMI≥27.5 Kg/m(2) ), and PNPLA3 148M allele (OR 6.03, CI 1.23-5.0 for each 148M allele). PNPLA3 148M alleles were associated with a progressive increase in severe steatosis in patients with acquired cofactors such severe overweight and a history of alcohol intake (p=0.005). Conclusion: in CHB patients, the PNPLA3 I148M polymorphism influences the susceptibility to steatosis, and, in particular when associated with severe overweight and alcohol intake, to severe steatosis. (HEPATOLOGY 2013.).Hepatology 04/2013; · 11.66 Impact Factor -
Article: Dietary Iron Overload Induces Visceral Adipose Tissue Insulin Resistance.
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ABSTRACT: Increased iron stores associated with elevated levels of the iron hormone hepcidin are a frequent feature of the metabolic syndrome. The aim of this study was to assess the effect of dietary iron supplementation on insulin resistance and the role of hepcidin in C57Bl/6 male mice fed a standard or iron-enriched diet for 16 weeks. Iron supplementation increased hepatic iron and serum hepcidin fivefold and led to a 40% increase in fasting glucose due to insulin resistance, as confirmed by the insulin tolerance test, and to threefold higher levels of triglycerides. Iron supplemented mice had lower visceral adipose tissue mass estimated by epididymal fat pad, associated with iron accumulation in adipocytes. Decreased insulin signaling, evaluated by the phospho-Akt/Akt ratio, was detected in the visceral adipose tissue of iron overloaded mice, and gene expression analysis of visceral adipose tissue showed that an iron-enriched diet up-regulated iron-responsive genes and adipokines, favoring insulin resistance, whereas lipoprotein lipase was down-regulated. This resulted in hyperresistinemia and increased visceral adipose tissue expression of suppressor of suppressor of cytokine signaling-3 (Socs3), a target of resistin and hepcidin implicated in insulin resistance. Acute hepcidin administration down-regulated lipoprotein lipase and up-regulated Socs3 in visceral adipose tissue. In conclusion, we characterized a model of dysmetabolic iron overload syndrome in which an iron-enriched diet induces insulin resistance and hypertriglyceridemia and affects visceral adipose tissue metabolism by a mechanism involving hepcidin up-regulation.American Journal Of Pathology 04/2013; · 4.89 Impact Factor -
Article: The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis.
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ABSTRACT: Aim of this study was to evaluate whether the A736V TMPRSS6 polymorphism, a major genetic determinant of iron metabolism in healthy subjects, influences serum levels of hepcidin, the hormone regulating iron metabolism, and erythropoiesis in chronic hemodialysis (CHD). To this end, we considered 199 CHD patients from Northern Italy (157 with hepcidin evaluation), and 188 healthy controls without iron deficiency, matched for age and gender. Genetic polymorphisms were evaluated by allele specific polymerase chain reaction assays, and hepcidin quantified by mass spectrometry. Serum hepcidin levels were not different between the whole CHD population and controls (median 7.1, interquartile range (IQR) 0.55-17.1 vs. 7.4, 4.5-17.9 nM, respectively), but were higher in the CHD subgroup after exclusion of subjects with relative iron deficiency (p = 0.04). In CHD patients, the A736V TMPRSS6 polymorphism influenced serum hepcidin levels in individuals positive for mutations in the HFE gene of hereditary hemochromatosis (p < 0.0001). In particular, the TMPRSS6 736 V variant was associated with higher hepcidin levels (p = 0.017). At multivariate analysis, HFE and A736V TMPRSS6 genotypes predicted serum hepcidin independently of ferritin and C reactive protein (p = 0.048). In patients without acute inflammation and overt iron deficiency (C reactive protein <1 mg/dl and ferritin >30 ng/ml; n = 86), hepcidin was associated with lower mean corpuscular volume (p = 0.002), suggesting that it contributed to iron-restricted erythropoiesis. In line with previous results, in patients without acute inflammation and severe iron deficiency the "high hepcidin" 736 V TMPRSS6 variant was associated with higher erythropoietin maintenance dose (p = 0.016), independently of subclinical inflammation (p = 0.02). The A736V TMPRSS6 genotype influences hepcidin levels, erythropoiesis, and anemia management in CHD patients. Evaluation of the effect of TMPRSS6 genotype on clinical outcomes in prospective studies in CHD may be useful to predict the outcomes of hepcidin manipulation, and to guide treatment personalization by optimizing anemia management.BMC Nephrology 01/2013; 14:48. · 2.18 Impact Factor -
Article: IL28B rs12979860 polymorphism influences serum TNFalpha levels in chronic hepatitis C.
Digestive and Liver Disease 11/2012; · 3.05 Impact Factor -
Article: The i148m Pnpla3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls.
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ABSTRACT: Reduced adiponectin is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), and the I148M Patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism predisposes to NAFLD and liver damage progression in NASH and chronic hepatitis C (CHC) by still undefined mechanisms, possibly involving regulation of adipose tissue function. Aim of this study was to evaluate whether the I148M PNPLA3 polymorphism influences serum adiponectin in liver diseases and healthy controls. To this end, we considered 144 consecutive Italian patients with NAFLD, 261 with CHC, 35 severely obese subjects, and 257 healthy controls with very low probability of steatosis, all with complete clinical and genetic characterization, including adiponectin (ADIPOQ) genotype. PNPLA3 rs738409 (I148M) and ADIPOQ genotypes were evaluated by Taqman assays, serum adiponectin by ELISA. Adiponectin mRNA levels were evaluated by quantitative real-time PCR in the visceral adipose tissue (VAT) of 35 obese subjects undergoing bariatric surgery. Adiponectin levels were independently associated with the risk of NAFLD and with the histological severity of the disease. Adiponectin levels decreased with the number of 148 M PNPLA3 alleles at risk of NASH both in patients with NAFLD (p = 0.03), and in healthy subjects (p = 0.04). At multivariate analysis, PNPLA3 148 M alleles were associated with low adiponectin levels (<6 mg/ml, median value) independently of NAFLD diagnosis, age, gender, BMI, and ADIPOQ genotype (OR 1.67, 95% c.i. 1.07-2.1 for each 148 M allele). The p.148 M PNPLA3 variant was associated with decreased adiponectin mRNA levels in the VAT of obese patients (p < 0.05) even in the absence of NASH. In contrast, in CHC, characterized by adiponectin resistance, low adiponectin was associated with male gender and steatosis, but not with PNPLA3 and ADIPOQ genotypes and viral features. The I148M PNPLA3 variant is associated with adiponectin levels in patients with NAFLD and in healthy subjects, but in the presence of adiponectin resistance not in CHC patients. The I148M PNPLA3 genotype may represent a genetic determinant of serum adiponectin levels. Modulation of serum adiponectin might be involved in mediating the susceptibility to steatosis, NASH, and hepatocellular carcinoma in carriers of the 148 M PNPLA3 variant without CHC, with potential therapeutic implications.BMC Gastroenterology 08/2012; 12:111. · 2.42 Impact Factor -
Article: Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease.
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD), defined by excessive liver fat deposition related to the metabolic syndrome, is a leading cause of progressive liver disease, for which accurate non-invasive staging systems and effective treatments are still lacking. Evidence has shown that increased ferritin levels are associated with the metabolic insulin resistance syndrome, and higher hepatic iron and fat content. Hyperferritinemia and iron stores have been associated with the severity of liver damage in NAFLD, and iron depletion reduced insulin resistance and liver enzymes. Recently, Kowdley et al demonstrated in a multicenter study in 628 adult patients with NAFLD from the NAFLD-clinical research network database with central re-evaluation of liver histology and iron staining that the increased serum ferritin level is an independent predictor of liver damage in patients with NAFLD, and is useful to identify NAFLD patients at risk of non-alcoholic steatohepatitis and advanced fibrosis. These data indicate that incorporation of serum ferritin level may improve the performance of noninvasive scoring of liver damage in patients with NAFLD, and that iron depletion still represents an attractive therapeutic target to prevent the progression of liver damage in these patients.World Journal of Gastroenterology 08/2012; 18(29):3782-6. · 2.47 Impact Factor -
Article: Effect of the A736V TMPRSS6 polymorphism on the penetrance and clinical expression of hereditary hemochromatosis.
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ABSTRACT: BACKGROUND & AIMS: Hereditary hemochromatosis (HH) is most frequently related to homozygosity for the p.C282Y HFE mutation (C282Y(+/+)), hampering hepcidin induction in response to iron. The rs855791 polymorphism, encoding for the p.A736V variant of TMPRSS6 regulating hepcidin, influences iron status in the population. The aim of this study was to assess the influence of rs855791 on the penetrance and clinical expression of HH. METHODS: We retrospectively considered 315 HH patients (163 C282Y(+/+), and 152 with other HFE genotypes) evaluated at the time of diagnosis, and 271 healthy controls with normal iron parameters, residents of Northern Italy; TMPRSS6 genotype was assessed by allele specific polymerase chain reaction. RESULTS: The p.736V variant determining higher hepcidin release was under-represented in the patients (p=0.0023), independently of the presence of the C282Y(+/+) genotype, and the p.736V/V genotype protected from HH independently of age and sex (OR of HH for p.736A/A: 2.57, 1.3-4.1 and for p.736A/V: 1.84, 1.1-3.2). In the 96 C282Y(+/+) male patients without chronic viral hepatitis and alcohol abuse, the "high hepcidin" p.736V allele was negatively associated with cirrhosis independently of age, ferritin, ALT levels, and alcohol intake (OR 3.93, 95% C.I. 1.17-14.61 for the p.736A variant), and with the cumulative incidence of hepatocellular carcinoma (17% p.736A/A, 4% p.736A/V, 0 p.736V/V, p=0.05). CONCLUSIONS: The p.A736V TMPRSS6 polymorphism is likely a modifier of HH expression. Additional studies are warranted to validate these findings in other cohorts and test their potential relevance for the clinical management of HH patients.Journal of Hepatology 08/2012; · 9.26 Impact Factor -
Article: CYBRD1 as a modifier gene that modulates iron phenotype in HFEp.c282y homozygous patients.
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ABSTRACT: Background. Most patients with Hereditary Hemochromatosis are homozygous for the p.C282Y mutation in the HFE gene in Caucasian population. Penetrance and expression of Hemochromatosis largely differ in p.C282Y homozygous cases. Besides environmental factors, genetic factors might be implicated. Design and Methods. In the present study, we analysed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 Italian p.C282Y homozygous cases. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. Results. We found a series of 17 genetic variants located in different genes with possible additive effect on the studied outcomes. In order to evaluate if the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction can be achieved adding genetic information to clinical data. Among the selected polymorphisms, a significant association between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation was observed. This variant belongs to the same haplotype block which contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. Luciferase assay indicates that rs3806562 has not a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. Conclusions. While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-HH, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of HH phenotype.Haematologica 07/2012; · 6.42 Impact Factor -
Article: Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis.
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ABSTRACT: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH). We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine aminotransaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 ± 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI ≥ 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin > 1000 ng/mL at diagnosis (OR 19.3, 95% CI: 5.3-125), and with the G allele in patients with BMI < 25 (OR 3.26, 95% CI: 1.3-10.3). The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH.World Journal of Gastroenterology 06/2012; 18(22):2813-20. · 2.47 Impact Factor -
Article: The A736V TMPRSS6 Polymorphism Influences Hepatic Iron Overload in Nonalcoholic Fatty Liver Disease.
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ABSTRACT: BACKGROUND #ENTITYSTARTX00026; AIMS: Hepatic iron accumulation due to altered trafficking is frequent in patients with nonalcoholic fatty liver disease (NAFLD), and is associated with more severe liver damage and hepatocellular carcinoma. The p.Ala736Val TMPRSS6 variant influences iron metabolism regulating the transcription of the hepatic hormone hepcidin, but its role in the pathogenesis of iron overload disorders is controversial. Aim of this study was to evaluate the whether the TMPRSS6 p.Ala736Val variant influences hepatic iron accumulation in a well-characterized series of Italian patients with histological NAFLD. METHODS: 216 patients with histological NAFLD. TMPRSS6 and HFE variants were assessed by allele specific PCR, liver histology by the NAFLD activity score and Perls' staining for iron. RESULTS: Homozygosity for the p.736Val allele previously linked to higher hepcidin did not influence transferrin saturation (TS), but was associated with lower hepatic iron stores (p = 0.01), and ferritin levels (median 223 IQR 102-449 vs. 308 IQR 141-618 ng/ml; p = 0.01). Homozygosity for TMPRSS6 p.736Val was nearly associated with lower ballooning (p = 0.05), reflecting hepatocellular damage related to oxidative stress. The influence of TMPRSS6 on hepatic iron accumulation was more marked in patients negative for HFE genotypes predisposing to iron overload (p.Cys282Tyr + and p.His63Asp +/+; p = 0.01), and the p.736Val variant was negatively associated with hepatic iron accumulation independently of age, gender, HFE genotype, and beta-thalassemia trait (OR 0.59, 0.39-0.88). CONCLUSIONS: The p.Ala736Val TMPRSS6 variant influences secondary hepatic iron accumulation in patients with NAFLD.PLoS ONE 01/2012; 7(11):e48804. · 4.09 Impact Factor -
Article: Gallstone disease is associated with more severe liver damage in patients with non-alcoholic fatty liver disease.
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) are both highly prevalent in the general population and associated with obesity and insulin resistance. We aimed to evaluate the prevalence of GD in a cross sectional study of NAFLD patients and to define whether the presence of GD is associated with diabetes and predicts more severe liver disease. We merged databases of four Liver Units, comprising 524 consecutive biopsy-proven NAFLD (373 males) observed between January 2003 and June 2010. GD was diagnosed in 108 (20%), and 313 cases (60%) were classified by liver biopsy as nonalcoholic steatohepatitis (NASH). The GD subgroup was characterized by a significantly higher prevalence of females, prediabetes/diabetes, abdominal obesity and metabolic syndrome, older age, higher BMI, fasting glucose, HOMA-IR and lower ALT. The prevalence of GD progressively increased with advancing fibrosis and with the severity of necroinflammatory activity (p for trend = 0.0001 and = 0.01, respectively), without differences in the severity of steatosis. At multivariate analysis GD was associated with female gender (OR 1.37, 95% CI 1.04-1.8), age (OR 1.027, 95% CI1.003-1.05), fasting glucose (OR 1.21, 95% CI 1.10-1.33) and NASH (OR 1.40,95% CI 1.06-1.89), whereas ALT levels were associated with a lower GD risk (OR 0.98, 95% CI 0.97-0.99). When subjects with cirrhosis were excluded from analysis, the association between GD and fasting glucose, female gender, and NASH was maintained. Patients with NAFLD have a high prevalence of GD, which characterizes subjects with altered glucose regulation and more advanced liver disease.PLoS ONE 01/2012; 7(7):e41183. · 4.09 Impact Factor -
Article: LPIN1 rs13412852 polymorphism in pediatric nonalcoholic fatty liver disease.
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ABSTRACT: The aim of the present study was to evaluate whether the lipin1 rs13412852 C>T polymorphism is associated with nonalcoholic steatohepatitis and fibrosis in pediatric Italian patients with nonalcoholic fatty liver disease (NAFLD). A total of 142 untreated, consecutive children and 115 adults with biopsy-proven NAFLD and 337 healthy controls without steatosis were studied. Liver histology was assessed by the NAFLD activity score and the rs13412852 polymorphism by a 5' nuclease Taqman assay. Homozygosity for the rs13412852 T allele was underrepresented in pediatric, but not adult, patients with NAFLD compared with healthy controls (7% vs 14%; odds ratio [OR] 0.58, 95% confidence interval [CI] 0.35-0.91), and it was associated with lower triglycerides both in pediatric patients and healthy controls (P ≤ 0.01). Affected children carrying the rs13412852 TT genotype had a trend for a lower prevalence of nonalcoholic steatohepatitis, and significantly less severe liver damage, as indicated by NAFLD activity score severity (P = 0.026) and a lower prevalence of liver fibrosis (P = 0.012). The negative association between rs13412852 TT genotype and fibrosis was independent of Patatin-like phospholipase domain-containing-3 genotype and other clinical risk factors, including age, waist circumference, the presence of hyperglycemia, and alanine transaminase levels (OR 0.29; 95% CI 0.11-0.66), and it was confirmed at multivariate analysis in adults (OR 0.15; 95% CI 0.02-0.67). Lipin1 rs13412852 single nucleotide polymorphism is associated with the severity of liver damage and fibrosis progression in pediatric patients with histological NAFLD.Journal of pediatric gastroenterology and nutrition 12/2011; 54(5):588-93. · 2.18 Impact Factor -
Article: Modulation of the effect of PNPLA3 I148M mutation on steatosis and liver damage by alcohol intake in patients with chronic hepatitis C.
Journal of Hepatology 12/2011; 55(6):1470-1; author reply 1471-2. · 9.26 Impact Factor -
Article: Patatin-like phospholipase domain containing-3 Ile148Met and fibrosis progression after liver transplantation.
Hepatology 08/2011; 54(4):1484. · 11.66 Impact Factor -
Article: The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver.
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ABSTRACT: The T-455C and C-482T APOC3 promoter region polymorphisms (SNPs) have recently been reported to predispose to dyslipidemia, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) in Indian subjects, but the association with liver damage has not been evaluated so far. The aim was to assess the association between APOC3 SNPs and liver damage in Caucasian patients. We considered 437 Italian patients with histological diagnosis of NAFLD (including 137 children, 120 morbid obese) and 316 healthy controls, 71 Italian family trios, and 321 patients from the UK. APOC3 SNPs were determined by sequencing, allele-specific oligonucleotide probes and PCR-restriction fragment length polymorphism analysis, hepatic APOC3 mRNA levels by real-time PCR. APOC3 SNPs were not associated with NAFLD in Italian subjects, although a borderline significance for the transmission of the -455T allele was observed in the family study. Homozygosity for the APOC3 wild-type genotype (APOC3 WT) was associated with a more favorable lipid profile in control subjects, and consistently with lower hepatic APOC3 mRNA levels in obese patients without diabetes. However, APOC3 SNPs, alone or in combination, were not associated with insulin resistance, altered lipid levels, liver enzymes, and with liver damage (severity of steatosis, nonalcoholic steatohepatitis, and moderate/severe fibrosis) in Italian as well as in UK patients, and in the whole cohort. Stratification for the I148M PNPLA3 mutation, associated with the susceptibility to NASH, did not alter the results. APOC3 genotype is not associated with progressive liver damage in Caucasian patients with NAFLD.Journal of Hepatology 07/2011; 55(6):1409-14. · 9.26 Impact Factor -
Article: The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies.
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ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a complex disease trait where genetic variations and environment interact to determine disease progression. The association of PNPLA3 with advanced disease has been consistently demonstrated but many other modifier genes remain unidentified. In NAFLD, increased fatty acid oxidation produces high levels of reactive oxygen species. Manganese-dependent superoxide dismutase (MnSOD), encoded by the SOD2 gene, plays an important role in protecting cells from oxidative stress. A common non-synonymous polymorphism in SOD2 (C47T; rs4880) is associated with decreased MnSOD mitochondrial targeting and activity making it a good candidate modifier of NAFLD severity. The relevance of the SOD2 C47T polymorphism to fibrotic NAFLD was assessed by two complementary approaches: we sought preferential transmission of alleles from parents to affected children in 71 family trios and adopted a case-control approach to compare genotype frequencies in a cohort of 502 European NAFLD patients. In the family study, 55 families were informative. The T allele was transmitted on 47/76 (62%) possible occasions whereas the C allele was transmitted on only 29/76 (38%) occasions, p=0.038. In the case control study, the presence of advanced fibrosis (stage>1) increased with the number of T alleles, p=0.008 for trend. Multivariate analysis showed susceptibility to advanced fibrotic disease was determined by SOD2 genotype (OR 1.56 (95% CI 1.09-2.25), p=0.014), PNPLA3 genotype (p=0.041), type 2 diabetes mellitus (p=0.009) and histological severity of NASH (p=2.0×10(-16)). Carriage of the SOD2 C47T polymorphism is associated with more advanced fibrosis in NASH.Journal of Hepatology 07/2011; 56(2):448-54. · 9.26 Impact Factor -
Article: Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target.
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ABSTRACT: The dysmetabolic iron overload syndrome (DIOS) is now a frequent finding in the general population, as is detected in about one third of patients with nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome. The pathogenesis is related to altered regulation of iron transport associated with steatosis, insulin resistance, and subclinical inflammation, often in the presence of predisposing genetic factors. Evidence is accumulating that excessive body iron plays a causal role in insulin resistance through still undefined mechanisms that probably involve a reduced ability to burn carbohydrates and altered function of adipose tissue. Furthermore, DIOS may facilitate the evolution to type 2 diabetes by altering beta-cell function, the progression of cardiovascular disease by contributing to the recruitment and activation of macrophages within arterial lesions, and the natural history of liver disease by inducing oxidative stress in hepatocytes, activation of hepatic stellate cells, and malignant transformation by promotion of cell growth and DNA damage. Based on these premises, the association among DIOS, metabolic syndrome, and NAFLD is being investigated as a new risk factor to predict the development of overt cardiovascular and hepatic diseases, and possibly hepatocellular carcinoma, but most importantly, represents also a treatable condition. Indeed, iron depletion, most frequently achieved by phlebotomy, has been shown to decrease metabolic alterations and liver enzymes in controlled studies in NAFLD. Additional studies are warranted to evaluate the potential of iron reductive therapy on hard clinical outcomes in patients with DIOS.Journal of Hepatology 06/2011; 55(4):920-32. · 9.26 Impact Factor -
Article: Diagnostic accuracy of clathrin heavy chain staining in a marker panel for the diagnosis of small hepatocellular carcinoma.
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ABSTRACT: The American Association for the Study of Liver Diseases guidelines recommend the use of all available markers for improving the accuracy of the diagnosis of small hepatocellular carcinoma (HCC). To determine whether clathrin heavy chain (CHC), a novel HCC marker, is effective in combination with glypican 3 (GPC3), heat shock protein 70, and glutamine synthetase, we compared the performances of a three-marker panel (without CHC) and a four-marker panel (with CHC) in a series of small HCCs (≤2 cm) and nonsmall HCCs by core biopsy with a 20- to 21-gauge needle. The series included 39 nonsmall HCCs and 47 small HCCs (86 in all); the latter showed a well-differentiated histology [small grade 1 (G1)] in 30 cases (63.8%). The panel specificity was analyzed with the adjacent/extranodular cirrhotic liver (n = 30) and low-grade (n = 15) and high-grade dysplastic nodules (n = 16) as a control group. Absolute specificity (100%) for HCC was obtained only when at least two of the markers were positive (which two markers were positive did not matter). The addition of CHC to the panel increased the diagnostic accuracy for small HCCs (from 76.9% to 84.3%), and there was an important gain in sensitivity (from 46.8% to 63.8%). The four-marker panel had lower rates of accuracy (67.4%) and sensitivity (50%) for small G1 HCCs versus nonsmall G1 HCCs (93.9% and 88.2%, respectively). In seven cases (including six small G1 HCCs), there was no staining with any of the markers. Cirrhotic control livers were stained for CHC in four cases (13.3%) and for GPC3 in one case (3.3%). CONCLUSION: The addition of CHC to the panel supports the diagnosis of small HCCs in challenging nodules on thin core biopsy samples. Small G1 HCCs include a group of earlier tumors characterized by a more silent phenotype and the progressive acquisition of the markers under study. The search for additional markers for early HCC diagnosis is warranted.Hepatology 05/2011; 53(5):1549-57. · 11.66 Impact Factor -
Article: Patatin‐like phospholipase domain‐containing protein 3 genotype and hepatocellular carcinoma in chronic hepatitis C
Hepatology 04/2011; 53(5):1777 - 1777. · 11.66 Impact Factor -
Article: Serum hepcidin and macrophage iron correlate with MCP-1 release and vascular damage in patients with metabolic syndrome alterations.
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ABSTRACT: Increased body iron stores and hepcidin have been hypothesized to promote atherosclerosis by inducing macrophage iron accumulation and release of cytokines, but direct demonstration in human cells is lacking. The aim of this study was to evaluate the effect of iron on cytokine release in monocytes ex vivo and the correlation with vascular damage and to evaluate the relationship among serum levels of hepcidin, cytokines, and vascular damage in patients with metabolic syndrome alterations. Manipulation of iron status with ferric ammonium citrate and hepcidin-25 induced monocyte chemoattractant protein (MCP)-1 and interleukin-6 in human differentiating monocytes of patients with hyperferritinemia associated with the metabolic syndrome (n=11), but not in subjects with hemochromatosis or HFE mutations impairing iron accumulation (n=15), and the degree of induction correlated with the presence of carotid plaques, detected by echocolor-Doppler. In monocytes of healthy subjects (n=7), iron and hepcidin increased the mRNA levels and release of MCP-1, but not of interleukin-6. In 130 patients with metabolic alterations, MCP-1 levels, as detected by ELISA, were correlated with hepcidin-25 measured by time-of-flight mass spectrometry (P=0.005) and were an independent predictor of the presence of carotid plaques (P=0.05). Hepcidin and macrophage iron correlate with MCP-1 release and vascular damage in high-risk individuals with metabolic alterations.Arteriosclerosis Thrombosis and Vascular Biology 03/2011; 31(3):683-90. · 6.37 Impact Factor
Top co-authors
Top Journals
Institutions
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2008–2012
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Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
- Internal Medicine 3
Milano, Lombardy, Italy -
Ospedale di San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico
Milano, Lombardy, Italy -
Università degli Studi del Sannio
Benevento, Campania, Italy
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1992–2012
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University of Milan
- • Department of Internal Medicine
- • Istituto di Scienze Dermatologiche
Milano, Lombardy, Italy
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