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Candidate Biomarkers of Liver Fibrosis: A Concise, Pathophysiology-oriented Review

Journal of Clinical and Translational Hepatology 2018年第3期6卷 317-325页

作者： Mattia Bellan Luigi mario Castello mario pirisi Department of Translational Medicine Universita del Piemonte Orientale UPONovaraItaly Division of Internal Medicine “Sant'Andrea Hospital”VercelliItaly IRCAD Interdisciplinary Research Center of Autoimmune DiseasesNovaraItaly Emergency Medicine Department “AOU Maggiore della Carita”NovaraItaly Division of Internal Medicine “AOU Maggiore della Carita”NovaraItaly

Repair of sustained liver injury results in fibrosis(i.***.the accumulation of extracellular matrix proteins),and ultimately the complete distortion of parenchymal architecture of the liver,which we call cirrhosis.Detecting and staging of fibrosis is thus a mainstay in the management of chronic liver diseases,since many clinically relevant decisions,such as starting treatment and/or monitoring for complications including hepatocellular carcinoma,may depend on it.The gold standard for fibrosis staging is liver biopsy,the role of which,however,is questioned nowadays because of cost,hazards and poor acceptance by patients.On the other hand,imaging techniques and/or measurement of direct and indirect serum markers have not proved to be completely satisfactory under all circumstances as alternatives to liver biopsy.Making progress in this field is nowmore crucial than ever,since treatments for established fibrosis appear on the horizon.Fine dissection of the pathways involved in the pathophysiology of liver diseases has put forward several novel candidate biomarkers of liver fibrosis,such as growth arrest-specific6,Mac-2-binding protein,osteopontin,placental growth factor,growth/differentiation factor 15 and hepatocyte growth factor.All molecules have been suggested to have potential to complement or substitute methods currently used to stage liver diseases.Here,we review the pros and cons for their use in this setting.

关键词： Liver fibrosis Staging Biomarkers Gas6 HGF PlGF

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Vitamin D receptor gene polymorphisms and hepatocellular carcinoma in alcoholic cirrhosis

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World Journal of Gastroenterology 2010年第24期16卷 3016-3024页

作者： Edmondo Falleti Davide Bitetto Carlo Fabris Annarosa Cussigh Elisabetta Fontanini Ezio Fornasiere Elisa Fumolo Sara Bignulin Sara Cmet Rosalba Minisini mario pirisi Pierluigi Toniutto Laboratory Medicine University of Udine Department of Medical Sciences Clinical and Experimental Medical Liver Transplant UnitUniversity of Udine Department of Clinical and Ex-perimental Medicine University of Eastern Piedmont "A. Avoga-dro"

AIM: To assess the relationship between vitamin D re-ceptor (VDR) gene polymorphisms and the presence of hepatocellular carcinoma (HCC). METHODS: Two-hundred forty patients who underwent liver transplantation were studied. The etiologies of liver disease were hepatitis C (100 patients), hepatitis B (37) and alcoholic liver disease (103). A group of 236 healthy subjects served as controls. HCC in the explanted liver was detected in 80 patients. The following single nucle-otide gene polymorphisms of the VDR were investigatedby polymerase chain reaction and restriction fragment length polymorphism: FokI C>T (F/f), BsmI A>G (B/b), ApaI T>G (A/a) and TaqI T>C (T/t) (BAT). RESULTS: The frequencies of genotypes in patients without and with HCC were for FokI F/F = 69, F/f = 73, f/f = 18 and F/F = 36, F/f = 36, f/f = 8; BsmI b/b = 45, B/b = 87, B/B = 28 and b/b = 33, B/b = 35, B/B = 12; for ApaI A/A = 53, A/a = 85, a/a = 22 and A/A = 27, A/a = 38, a/a = 15; for TaqI T/T = 44, T/t = 88, t/t = 28 and T/T = 32, T/t = 38, t/t = 10. Carriage of the b/b genotype of BsmI and the T/T genotype of TaqI was signif icantly associated with HCC (45/160 vs 33/80, P < 0.05 and 44/160 vs 32/80, P < 0.05, respectively). The absence of the A-T-C protective allele of BAT was signif i-cantly associated with the presence of HCC (46/80 vs 68/160, P < 0.05). A strong association was observed between carriage of the BAT A-T-C and G-T-T haplotypes and HCC only in alcoholic liver disease (7/46 vs 12/36 vs 11/21, P < 0.002, respectively).CONCLUSION: VDR genetic polymorphisms are sig-nificantly associated with the occurrence of HCC in patients with liver cirrhosis. This relationship is more specific for patients with an alcoholic etiology.

关键词： Alcohol Hepatocellular carcinoma Liver cirrhosis Vitamin D receptor polymorphisms

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Finding the seed of recurrence:Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment

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World Journal of Gastrointestinal Surgery 2021年第9期13卷 967-978页

作者： Francesca Carissimi Matteo Nazzareno Barbaglia Livia Salmi Cristina Ciulli Linda Roccamatisi Giuseppe Cordaro Venkata Ramana Mallela Rosalba Minisini Biagio Eugenio Leone Matteo Donadon Guido Torzilli mario pirisi Fabrizio Romano Simone Famularo School of Medicine and Surgery University of Milano-BicoccaMonza 20900Italy Department of Translational Medicine Universitàdel Piemonte OrientaleNovara 28100Italy Unit of Pathology San Gerardo HospitalMonza 20900Italy Department of Hepatobiliary and General Surgery IRCCS Humanitas Clinical and Research Hospital-Department of Biomedical ScienceHumanitas UniversityPieve Emanuele 20090Italy Department of Medicine and Surgery University of Milan-BicoccaMonza 20900Italy

The treatment for hepatocellular carcinoma(HCC)relies on liver resection,which is,however,burdened by a high rate of recurrence after surgery,up to 60%at 5 years.No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient.Recently liquid biopsy has shown interesting results in diagnosis,prognosis and treatment allocation strategies in other types of cancers,since its ability to identify circulating tumor cells(CTCs)derived from the primary tumor.Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC.In fact,after being modified by the epithelial-mesenchymal transition,CTCs circulate as“seeds”in peripheral blood,then reach the target organ as dormant cells which could be subsequently“awakened”and activated,and then initiate metastasis.Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections,particularly in the case of microvascular invasion,which has been recently pointed as a histological sign of the spread of those cells.Thus,their presence,also in the early stages,may justify the recurrence event also in the contest of liver transplant.Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics.Moreover,it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies,and in perspective,it could also become a new method to allocate organs for transplantation,according to the risk of relapse after liver transplant.The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC,highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.

关键词： Hepatocellular carcinoma Liquid biopsy Circulating tumor cells Liver surgery Microvascular invasion Hepatocellular carcinoma recurrence

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Excess body weight, liver steatosis, and early fibrosis progression due to hepatitis C recurrence after liver transplantation

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World Journal of Gastroenterology 2005年第38期11卷 5944-5950页

作者： Pierluigi Toniutto Carlo Fabris Claudio Avellini Rosalba Minisini Davide Bitetto Elisabetta Rossi Carlo Smirne mario pirisi Liver Transplantation Unit Pathology Department of Medical Sciences

AIM: To investigate how weight gain after OLT affects the speed of fibrosis progression (SFP) during recurrent hepatitis C virus (HCV) infection of the graft.METHODS: Ninety consecutive patients (63 males,median age 53 years; 55 with HCV-related liver disease),transplanted at a single institution, were studied. All were followed for at least 2 years after OLT and had at least one follow-up graft biopsy, performed not earlier than 1 year after the transplant operation. For each biopsy, a single,experienced pathologist gave an estimate of both the staging according to Ishak and the degree of hepatic steatosis.The SFP was quantified in fibrosis units/month (FU/mo).The lipid metabolism status of patients was summarized by the plasma triglycerides/cholesterol (T/C) ratio. Body mass index (BMI) was measured before OLT, and 1 and 2 years after it.RESULTS: In the HCV positive group, the highest SFP was observed in the first post-OLT year. At that time point,a SFP ≤0.100 FU/mo was observed more frequently among recipients who had received their graft from a young donor and had a pre-transplant BMI value ＞26.0 kg/m2. At completion of the first post-transplant year, a BMI value ＞26.5 kg/m2 was associated with a T/C ratio ≤1. The proportion of patients with SFP ＞0.100 FU/mo descended in the following order: female recipients with a high T/C ratio, male recipients with high T/C ratio, and recipients of either gender with low T/C ratio. Hepatic steatosis was observed more frequently in recipients who, in the first post-transplant year, had increased their BMI ≥1.5 kg/m2 in comparison to the pre-transplant value. Hepatic steatosis was inversely associated with the staging score.CONCLUSION: Among HCV positive recipients, excessweight gain post-OLT does not represent a factor favoring early liver fibrosis development and might even be protective against it.

关键词：体重脂肪肝肝纤维化丙型肝炎肝移植

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Response rates to direct antiviral agents among hepatitis C virus infected patients who develop hepatocellular carcinoma following direct antiviral agents treatment

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Hepatoma Research 2020年第2期6卷 1-10页

作者： Michela Emma Burlone Stefano Fangazio Alessandro Croce Elisa Ceriani Rachele Rapetti Cristina Rigamonti Carlo Smirne Stelvio Tonello Paolo Ravanini Rosalba Minisini mario pirisi Internal Medicine Azienda Ospedaliero-Universitaria Maggiore della CaritàNovara 28100Italy Department of Translational Medicine Universitàdel Piemonte OrientaleNovara 28100Italy Laboratory of Virology Azienda Ospedaliero-Universitaria Maggiore della CaritàNovara 28100Italy

Aim:Patients with chronic hepatitis C virus(HCV)infection who develop hepatocellular carcinoma(HCC)soon after treatment with direct antiviral agents(DAA)may have been harboring hitherto hidden tumors.If this were true,they should have a lower sustained viral response(SVR)rate,since active HCC hampers DAA efficacy.We aimed to verify this hypothesis.Methods:We included all patients who attended an HCV clinic,provided that they:(1)had no previous history of HCC;(2)had received at least one DAA dose;and(3)had been followed-up clinically and ultrasonographically for at least six months after concluding DAA.Results:The study population included n=789 patients(55%males,median age 62 years).A median of 9.3 months(8.8-11.9)after concluding DAA,n=19(2.4%)patients were discovered to harbor HCC.In comparison to all others,patients with HCC were more commonly male(84%vs.54%,P=0.009),obese(47%vs.17%,P=0.002),and cirrhotic(95%vs.35%,P<0.001)and had less commonly achieved an SVR(68%vs.98%,P<0.001).Moreover,they had a trend for being less commonly treatment na?ve(58%vs.67%,P=0.051).Based on multivariate analysis, ;the independent predictors of HCC were male sex(P=0.031),cirrhosis(P=0.004),obesity(P=0.006),and failure to achieve an SVR(P<0.001).Conclusion:Lack of achieving SVR is a strong independent predictor of development of HCC early after treatment of hepatitis C with DAA.Treatment failure should further alert clinicians to the possibility of this dreadful complication.

关键词： Chronic hepatitis C direct antiviral agent sustained viral response hepatocellular carcinoma obesity cirrhosis

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Effects of Cold Storage on Quality Traits of Sardinian Myrtle （Myrtus communis L.） Berries and Their Alcoholic Extracts

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Journal of Agricultural Science and Technology(B) 2011年第6期1卷 790-798页

作者： A. Angioni F. pirisi P. Caboni S. D＇Aquino A. Fadda M. Schirra Department of Toxycology Food and Environmental Unit University of Cagliari via Ospedale 72 Cagliari 09124 Italy Institute of Sciences of Food Production National Research Council Traversa La Crucca 3 Regione Baldinca. Li Punti 07040 Sassari Italy

Myrtus communis L. is a spontaneous aromatic plant typical of the Mediterranean area. Myrtle berries hydrodistilled products and ethanolic extracts are mainly used as flavouring agents and food supplements. This study evaluated the effect of long-term storage on the quality-related properties of myrtle berries. Storage at 2 °C for three months effectively preserved myrtle berries quality, both in the chemical composition and external appearance. No symptoms of chilling injury and decay occurred during the first two months of storage, at the end of storage only the 1.3% of rotting was detected. Total anthocyanic content and anthocyanin glycosides diminished whereas the antioxidant capacity increased in all samples till the end of storage. The antioxidant properties of myrtle berries were not correlated with the anthocyanic fraction. The pH of myrtle berries decreased, while gluconic acid levels increased. The results reported in this paper showed that the storage at 2 °C for three months appears to be an effective way to preserve myrtle berries quality. The changes in the chemical composition of the fruits subjected to storage had revealed the importance of gluconic acid and pH for myrtle quality assessment. These two parameters can be used as quality markers since a strong relationship has been found between myrtle decay and the changes in these parameters.

关键词：乙醇提取物浆果品质性状撒丁岛外观质量冷库酒精长期储存

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在转氨酶正常的丙肝病毒携带者中,两种无创性方法检测肝纤维化进展的价值

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世界核心医学期刊文摘（胃肠病学分册） 2006年第3期2卷 51-52页

作者： Colletta C. Smirne C. Fabris C. M. pirisi 李翔 Departimento di Scienze Mediche Università degli Studi del Piemonte Oriemale Amedeo Avogadro via Solaroli 17 28100 Novara Italy.Prof

The course of hepatitis C virus (HCV) infection carriers with normal/near-normal aminotransferases (NALT) is usually mild; however, in a few, fibrosis progression occurs. We aimed to verify whether monitoring by liver biopsy might be replaced by noninvasive methods and to identify factors associated with fibrosis progression in patients with persistently normal alanine aminotransferases. We studied 40 untreated HCV-RNA-positive subjects (22 male; median age, 44 years), who underwent two liver biopsies, with a median interval of 78.5 months, during which alanine aminotransferase concentrations (median number of determinations: 12) never exceeded 1.2 times the upper normal limit. Within 9 months from the second biopsy, they were tested by the shear elasticity probe (Fibroscan) and the artificial intelligence algorithm FibroTest. METAVIR fibrosis scores were analyzed in relationship to demographic, clinical, and viral parameters. Weighted kappa analysis was used to verify whether the results of noninvasive methods agreed with histology. Significant fibrosis (≥F2), present at the first biopsy in only one patient (2.5%), was observed at the second biopsy in 14 patients (35%). At multivariate analysis, excess alcohol consumption in the past (>20 g/d; P = .017) and viral load (>8.0 ×106 copies/mL; P = .021) were independent predictors of progression. In identifying patients with significant fibrosis, inter-rater agreement was excellent for Fibroscan (weighted kappa = 1.0), and poor for FibroTest (weighted kappa = -0.041). In conclusion, among HCV carriers with NALT, Fibroscan is superior to the FibroTest in the noninvasive identification of fibrosis, for which excess alcohol consumption in the past and high viral load represent risk factors.

关键词：肝纤维化携带者丙肝病毒无创性方法肝组织活检丙型肝炎病毒酗酒史正常上限病毒载量无创性

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