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| 1 | Hepatocellular carcinoma in nonalcoholic fatty liver: Role of environmental and genetic factors显示文摘Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools. | Paola Dongiovanni Stefano Romeo Luca Valenti | 2014 | World Journal of Gastroenterology2014，20，36： | 38 |
| 2 | PNPLA3 I148M polymorphism and progressive liver disease显示文摘The 148 Isoleucine to Methionine protein variant(I148M)of patatin-like phospholipase domain-containing 3(PNPLA3),a protein is expressed in the liver and is involved in lipid metabolism,has recently been identified as a major determinant of liver fat content.Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver:from simple steatosis to steatohepatitis and progressive fibrosis.Furthermore,the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis,and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis,and possibly chronic hepatitis B virus hepatitis,hereditary hemochromatosis and primary sclerosing cholangitis.All in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases.Remarkably,the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation,suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes,directly promoting fibrogenesis.Therefore,PNPLA3 is a key player in liver disease progression.Assessment of the I148M polymorphism will possibly inform clinical practice in the future,whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis. | Paola Dongiovanni Benedetta Donati Roberta Fares Rosa Lombardi Rosellina Margherita Mancina Stefano Romeo Luca Valenti | 2013 | World Journal of Gastroenterology2013，19，41： | 17 |
| 3 | Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease显示文摘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. | Luca Valenti Paola Dongiovanni Silvia Fargion | 2012 | World Journal of Gastroenterology2012，18，29： | 15 |
| 4 | A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia显示文摘AIM:To compare iron depletion to lifestyle changes alone in patients with severe nonalcoholic fatty liver disease(NAFLD)and hyperferritinemia,a frequent feature associated with more severe liver damage,despite at least 6 mo of lifestyle changes.METHODS:Eligible subjects had to be 18-75 years old who underwent liver biopsy for ultrasonographically detected liver steatosis and hyperferritinemia,ferritin levels≥250 ng/mL,and NAFLD activity score>1.Iron depletion had to be achieved by removing 350 cc of blood every 10-15 d according to baseline hemoglobin values and venesection tolerance,until ferritin<30 ng/mL and/or transferrin saturation(TS)<25%.Thirty-eight patients were randomized 1:1 to phlebotomy(n=21)or lifestyle changes alone(n=17).The main outcome of the study was improvement in liver damage according to the NAFLD activity score at 2 years,secondary outcomes were improvements in liver enzymes[alanine aminotransferases(ALT),aspartate aminotransferase(AST),and gamma-glutamyl-transferases(GGT)].RESULTS:Phlebotomy was associated with normalization of iron parameters without adverse events.In the21 patients compliant to the study protocol,the rate of histological improvement was higher in iron depleted vs control subjects(8/12,67%vs 2/9,22%,P=0.039).There was a better improvement in steatosis grade in iron depleted vs control patients(P=0.02).In patients followed-up at two years(n=35),ALT,AST,and GGT levels were lower in iron-depleted than in control patients(P<0.05).The prevalence of subjects with improvement in histological damage or,in the absence of liver biopsy,ALT decrease≥20%(associated with histological improvement in biopsied patients)was higher in the phlebotomy than in the control arm(P=0.022).The effect of iron depletion on liver damage improvement as assessed by histology or ALT decrease≥20%was independent of baseline AST/ALT ratio and insulin resistance(P=0.0001).CONCLUSION:Iron depletion by phlebotomy is likely associated with a higher rate of improvement of histological liver damage than lifestyle changes alone in patients with NAFLD and hyperferritinemia,and with amelioration of liver enzymes. | Luca Valenti Anna Ludovica Fracanzani Paola Dongiovanni Serena Rovida Raffaela Rametta Erika Fatta Edoardo Alessandro Pulixi Marco Maggioni Silvia Fargion | 2014 | World Journal of Gastroenterology2014，20，11： | 8 |
| 5 | Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis显示文摘AIM: 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). METHODS: 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. RESULTS: 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 amino-transaminase (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). CONCLUSION: The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH. | Luca Valenti Paolo Maggioni Alberto Piperno Raffaela Rametta Sara Pelucchi Raffaella Mariani Paola Dongiovanni Anna Ludovica Fracanzani Silvia Fargion | 2012 | World Journal of Gastroenterology2012，18，22： | 4 |
| 6 | HFE Genotype, Parenchymal Iron Accumulation, and Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease显示文摘 | Luca Valenti Anna Ludovica Fracanzani Elisabetta Bugianesi Paola Dongiovanni Enrico Galmozzi Ester Vanni Elena Canavesi Ezio Lattuada Giancarlo Roviaro Giulio Marchesini Silvia Fargion | 2010 | Gastroenterology2010，，3： | 4 |
| 7 | Dietary Iron Overload Induces Visceral Adipose Tissue Insulin Resistance显示文摘 | Paola Dongiovanni Massimiliano Ruscica Raffaela Rametta Stefania Recalcati Liliana Steffani Stefano Gatti Domenico Girelli Gaetano Cairo Paolo Magni Silvia Fargion Luca Valenti | 2013 | The American Journal of Pathology2013，，6： | 3 |
| 8 | The SOD2 C47T polymorphism influences NAFLD fibrosis severity: Evidence from case-control and intra-familial allele association studies显示文摘 | Ahmad Al-Serri Quentin M. Anstee Luca Valenti Valerio Nobili Julian B.S. Leathart Paola Dongiovanni Julia Patch Anna Fracanzani Silvia Fargion Christopher P. Day Ann K. Daly | 2011 | Journal of Hepatology2011，，2： | 2 |
| 9 | Statin use and non-alcoholic steatohepatitis in at risk individuals显示文摘 | Paola Dongiovanni Salvatore Petta Ville Mannisto Rosellina Margherita Mancina Rosaria Pipitone Vesa Karja Marco Maggioni Pirjo Kakela Olov Wiklund Enrico Mozzi Stefania Grimaudo Dorota Kaminska Raffaela Rametta Antonio Craxi Silvia Fargion Valerio Nobili | 2015 | Journal of Hepatology2015，，3： | 2 |
| 10 | Iron in fatty liver and in the metabolic syndrome: A promising therapeutic target显示文摘 | Paola Dongiovanni Anna Ludovica Fracanzani Silvia Fargion Luca Valenti | 2011 | Journal of Hepatology2011，，4： | 2 |
| 11 | Genetic Predisposition in NAFLD and NASH: Impact on Severity of Liver Disease and Response to Treatment显示文摘 | Paola Dongiovanni Quentin M. Anstee Luca Valenti | 2013 | Current Pharmaceutical Design2013，，29： | 2 |
| 12 | Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis显示文摘 | Valenti L Rametta R Dongiovanni P | | 0，，： | 1 |
| 13 | Iron in fatty liver and in the metabolic syndrome:a promising therapeutic target显示文摘 | Dongiovanni P Fracanzani AL Fargion S | | 0，，： | 1 |
| 14 | Alpha 1-an-titrypsin mutations in NAFLD: high prevalence and asso-ciation with altered iron metabolism but not with liverdamage 显示文摘 | Valenti L Dongiovanni P Pipemo A | 2006 | Hepatology2006，44，4： | 1 |
| 15 | Serum hepcidin and macrophage iron correlate with NCP-1 release and vascular damage in patients with metabolic syndrome alterations显示文摘 | Valenti L Dongiovanni P Motta BM | | 0，，： | 1 |
| 16 | Prospective evaluation of major vascular events in patients with nonsmall cell lung carcinoma treated with cisplatin and gemcitabine 显示文摘 | Numico G Garrone O Dongiovanni V | 2005 | Cancer2005，103，5： | 1 |
| 17 | Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis显示文摘 | Valenti L Rametta R Dongiovanni P | | 0，，： | 1 |
| 18 | Experimental Validation of a Common-Rail Injector Model in the Whole Operation Field显示文摘 | Marco Coppo Claudio Dongiovanni | 2007 | Transactions of the ASME2007，129，8： | 1 |
| 19 | Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease显示文摘 | Dongiovanni P Valenti L Rametta R | 2010 | Gut2010，59，2： | 1 |
| 20 | 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显示文摘 | Luca Valenti Valerio Nobili Ahmad Al-Serri Raffaela Rametta Julian B.S. Leathart Marco A. Zappa Paola Dongiovanni Anna L. Fracanzani Arianna Alterio Giancarlo Roviaro Ann K. Daly Silvia Fargion Christopher P. Day | 2011 | Journal of Hepatology2011，，6： | 1 |
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