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World Journal of Gastroenterology 2012年第29期18卷 3782-3786页

作者： Luca Valenti paola dongiovanni Silvia Fargion Università degli Studi di Milano Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico20122 MilanoItaly

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 *** has shown that increased ferritin levels are associated with the metabolic insulin resistance syndrome,and higher hepatic iron and fat *** and iron stores have been associated with the severity of liver damage in NAFLD,and iron depletion reduced insulin resistance and liver ***,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 *** 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.

关键词： Fibrosis Ferritin Iron overload Nonalcoholic fatty liver disease Steatohepatitis Steatosis

Hepatocellular carcinoma in nonalcoholic fatty liver: Role of environmental and genetic factors

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World Journal of Gastroenterology 2014年第36期20卷 12945-12955页

作者： paola dongiovanni Stefano Romeo Luca Valenti Internal Medicine 1B Fondazione IRCCS Ca’ Granda Ospedale Policlinico 20122 Milano Italy Department of Pathophysiology and Transplantation Università degli Studi di Milano 20122 Milano Italy Wallenberg Laboratory Department of Molecular and Clinical Medicine University of Gothenburg 40530 Gothenburg Sweden Clinical Nutrition Unit Department of Medical and Surgical Sciences University Magna Graecia 88100 Catan-zaro Italy

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.

关键词： Nonalcoholic fatty liver disease Steatosis Hepatocellular carcinoma Cirrhosis Fibrogenesis Liver disease Genetics Single nucleotide polymorphism Patatin-like phospholipase domain-containing 3

Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis

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World Journal of Gastroenterology 2012年第22期18卷 2813-2820页

作者： Luca Valenti Paolo Maggioni Alberto Piperno Raffaela Rametta Sara Pelucchi Raffaella Mariani paola dongiovanni Anna Ludovica Fracanzani Silvia Fargion Università degli Studi di Milano Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico 20122 Milano Italy Università di Milano Bicocca Ospedale San Gerardo Monza 20090 Monza MI Italy

AIM： To investigate whether the patatin-/ike phosph- olipase 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 ul- trasound （n = 23）. The PNPLA3 rs738409 single nucle- otide 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 pres- ence 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）, ferri

关键词： Fatty liver Fibrosis Hemochromatosis HFEprotein Iron overload Patatin-like phospholipase domaincontaining-3 gene Steatosis

Salivary biomarkers: novel noninvasive tools to diagnose chronic inflammation

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International Journal of Oral Science 2023年第2期15卷 229-240页

作者： paola dongiovanni Marica Meroni Sara Casati Riccardo Goldoni Douglas Vieira Thomaz Nermin Seda Kehr Daniela Galimberti Massimo Del Fabbro Gianluca MTartaglia Medicine and Metabolic Diseases Fondazione IRCCS CàGranda Ospedale Maggiore Policlinico Department of Biomedical Surgical and Dental SciencesUniversity of Milan Department of Electronics Information and Bioengineering(DEIB) Istituto di Elettronica e di Ingegneria dell'Informazione e delle Telecomunicazioni CNR Laboratory of Medicinal Pharmaceutical Chemistry Faculty of PharmacyFederal University of Goiás Department of Chemistry ?zmir Institute of TechnologyGülbah?e Kampüsü Neurology-Neurodegenerative Diseases Fondazione IRCCS CàGrandaOspedale Maggiore Policlinico UOC Maxillo-Facial Surgery and Dentistry Fondazione IRCCS CàGranda Ospedale Maggiore Policlinico

Several chronic disorders including type 2 diabetes(T2D),obesity,heart disease and cancer are preceded by a state of chronic lowgrade *** for the early assessment of chronic disorders encompass acute phase proteins(APP),cytokines and chemokines,pro-inflammatory enzymes,lipids and oxidative stress *** substances enter saliva through the blood flow and,in some cases。

关键词： inflammation acute chronic

A novel alpha1-antitrypsin null variant (PiQ0_(Milano))

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World Journal of Hepatology 2013年第8期5卷 458-461页

作者： Raffaela Rametta Gabriella Nebbia paola dongiovanni Marcello Farallo Silvia Fargion Luca Valenti Department of Pathophysiology and Transplantation Università degli Studi di Milano Internal Medicine Fondazione IRCCS Ca’ Granda Ospedale Policlinico Milano Pediatric Clinic Fondazione IRCCS Ca’ Granda Ospedale Policlinico

Alpha1-antitrypsin deficiency is an autosomal recessive disease characterized by reduced serum levels of alpha1-antitrypsin(AAT)due to mutations in the SERPINA1 gene causing early onset pulmonary emphysema and,occasionally,chronic liver *** report an incidental finding of a novel null AAT allele,Q0Milano,consisting of a 17 nucleotides deletion in exon 3 of SERPINA1 gene,in an Italian child with persistently increased liver enzymes,a mild decrease in circulating AAT levels and without any pulmonary disease.Q0Milano variant results in an unfunctional protein lacking of AAT active site,as the resultant protein is truncated near PiS locus involved in AAT protein stability.

关键词： Alpha1-antitrypsin deficiency Rare variant Alpha1-antitrypsin null mutation Liver disease

Old-fashioned and newly discovered biomarkers:the future of NAFLD-related HCC screening and monitoring

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Hepatoma Research 2022年第1期8卷 415-434页

作者： Roberto Piciotti Miriam Longo Adele Agresta Erika Paolini Annalisa Cespiati Marica Meroni paola dongiovanni General Medicine and Metabolic Diseases Fondazione IRCCS Ca’Granda Ospedale Maggiore PoliclinicoMilan 20122Italy Department of Pathophysiology and Transplantation Universitàdegli Studi di MilanoMilano 20122Italy Department of Clinical Sciences and Community Health Universitàdegli Studi di MilanoMilano 20122Italy Department of Pharmacological and Biomolecular Sciences Universitàdegli Studi di MilanoMilano 20133Italy

Nonalcoholic fatty liver disease(NAFLD)is the major contributor to the global burden of chronic liver diseases and ranges from simple and reversible steatosis to nonalcoholic steatohepatitis(NASH),which may progress into cirrhosis and hepatocellular carcinoma(HCC).HCC represents the most common liver cancer,and it is a leading cause of death worldwide with an increasing trend for the *** to late diagnosis,non-responsiveness to systemic therapy,and high cancer heterogeneity,the treatment of this malignancy is *** date,liver biopsy and ultrasound(US)are the gold standard procedures for HCC diagnosis and surveillance,although they are not suitable for mass ***,it is impelling to find new,less invasive diagnostic strategies able to detect HCC at an early stage as well as monitor tumor progression and *** and rare inherited variations that boost the switching from NASH to liver cancer may help to predict tumor ***,epigenetic changes which reflect intertumoral heterogeneity occur early in tumorigenesis and are highly stable under pathologic *** severity of hepatic injuries can be detected through the analysis of cell circulating tumor DNAs(ctDNAs),microRNAs(miRNAs),and noncoding RNAs(ncRNAs),which are involved in several pathological processes that feature cancer,including cell growth,survival,and differentiation,thus representing appealing biomarkers for ***,this review discusses the current options for HCC surveillance,focusing on the role of genetic and epigenetic biomarkers as new strategies to refine HCC management.

关键词： NAFLD-HCC screening genetic biomarkers ncRNAs epigenetics early HCC detection

A randomized trial of iron depletion in patients with nonalcoholic fatty liver disease and hyperferritinemia

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World Journal of Gastroenterology 2014年第11期20卷 3002-3010页

作者： Luca Valenti Anna Ludovica Fracanzani paola dongiovanni Serena Rovida Raffaela Rametta Erika Fatta Edoardo Alessandro Pulixi Marco Maggioni Silvia Fargion Department of Pathophysiology and Transplantation Metabolic Liver Diseases Research CenterUniversità degli Studi di MilanoFondazione IRCCS Ca' Granda Ospedale Policlinicovia F Sforza 3520122MilanoItaly

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... 详细信息

关键词： Nonalcoholic fatty liver disease Iron depletion Randomized controlled trial Ferritin

PNPLA3 I148M polymorphism and progressive liver disease

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World Journal of Gastroenterology 2013年第41期19卷 6969-6978页

作者： paola dongiovanni Benedetta Donati Roberta Fares Rosa Lombardi Rosellina Margherita Mancina Stefano Romeo Luca Valenti Internal Medicine Fondazione IRCCS Ca’ Granda Ospedale Policlinico MilanoDepartment of Pathophysiology and TransplantationUniversità degli Studi di Milano20122 MilanoItaly Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory Department of Molecular and Clinical MedicineUniversity of Gothenburg40530 GothenburgSweden Clinical Nutrition Unit Department of Medical and Surgical SciencesUniversity Magna Graecia88100 CatanzaroItaly

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 *** 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 ***,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 *** in all,studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver ***,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 ***,PNPLA3 is a key player in liver disease *** 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.

关键词： Alcoholic liver disease Chronic hepatitis C virus hepatitis Fibrogenesis Genetics Hepatocellular carcinoma Liver disease Nonalcoholic fatty liver disease Patatin-like phospholipase domain-containing 3 Single nucleotide polymorphism Steatosis