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Coagulation and Endothelial Dysfunction Associated with NAFLD:Current Status and Therapeutic Implications

Journal of Clinical and Translational Hepatology 2022年第2期10卷 339-355页

作者： Doris Ogresta Anna Mrzljak Maja Cigrovski Berkovic Ines Bilic-Curcic Sanja Stojsavljevic-Shapeski lucija virovic-jukic Department of Gastroenterology and Hepatology Sestre Milosrdnice University Hospital CenterZagrebCroatia Depart-ment of Gastroenterology and Hepatology University Hospital Center ZagrebZagrebCroatia Department of Medicine University of ZagrebSchool of MedicineZagrebCroatia Department for Endocrinology Diabetes and PharmacologyUniversity Hospital DubravaZagrebCroatia Department of Kinesiological Anthropology and Methodology Faculty of KinesiologyUniversity of Zagreb Department of Pharmacology Faculty of MedicineUniversity of JJ StrossmayerOsijekCroatia Department of Diabetes Endocrinology and Metabolism DisordersUniversity Hospital OsijekOsijekCroatia

Non-alcoholic fatty liver disease(NAFLD)is closely related to insulin resistance,type 2 diabetes mellitus,and *** is nowadays considered a multisystem disease with a strong association with cardiovascular disease and arterial hypertension,which interfere with changes in the coagulation *** disorders are common in patients with hepatic impairment and are dependent on the degree of liver *** with NAFLD may have preserved overall hemostatic profile,but many studies suggest a trend toward a procoagulant *** state in NAFLD patients may even induce progression of hepatic *** dysfunction is present in the systemic and portal vein circulation in NAFLD patients,and platelets are being recognized as modulators of liver diseases through various *** a literature review,we discuss possible disorders in the coagulation cascade and fibrinolysis,endothelial dysfunction,and platelet abnormalities in patients with *** the processes and mechanisms involved in the hemostatic abnormalities associated with NAFLD,directly related to liver disease or indirectly related through inflam-matory processes and metabolic disorders,several potential therapeutic targets have been identified and reviewed here.

关键词： Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis Insulin resistance Coagulation Endothelial dysfunction Platelet dysfunction Thrombosis

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Liver regeneration as treatment target for severe alcoholic hepatitis

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World Journal of Gastroenterology 2022年第32期28卷 4557-4573页

作者： lucija virovic-jukic Dominik Ljubas Sanja Stojsavljevic-Shapeski Neven Ljubičić Tajana Filipec Kanizaj Ivana Mikolasevic Ivica Grgurevic Department of Gastroenterology and Hepatology Sisters of Charity University Hospital CenterZagreb 10000Croatia Department of Internal Medicine University of Zagreb School of MedicineZagreb 10000Croatia Department of Internal Medicine University of Zagreb School of Dental MedicineZagreb 10000Croatia Department of Gastroenterology Merkur University HospitalZagreb 10000Croatia Department of Gastroenterology Rijeka University Hospital CenterRijeka 51000Croatia Department of Internal Medicine University of Rijeka School of MedicineRijeka 10000Croatia Department of Gastroenterology Hepatology and Clinical NutritionDubrava University HospitalZagreb 10000Croatia

Severe alcoholic hepatitis(AH)is a distinct entity in the spectrum of alcoholrelated liver disease,with limited treatment options and high *** medical care with corticosteroids in selected patients is the only currently available treatment option,often with poor *** on the insights into the pathogenetic mechanisms of AH,which are mostly obtained from animal studies,several new treatment options are being *** have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic *** evidence for the beneficial effects of granulocyte colony-stimulating factor(G-CSF)on liver regeneration and immunomodulation in animal models,several human studies investigated its role in the treatment of advanced alcohol-related liver disease and *** to the previously published studies suggesting benefits of G-CSF in the outcomes of patients with severe AH,these effects were not confirmed by a recently published multicenter randomized trial,suggesting that other options should rather be *** cell transplantation represents another option for improving liver regeneration,but evidence for its efficacy in patients with severe AH and advanced alcohol-related liver disease is still very scarce and unconvincing,with established lack of efficacy in patients with compensated *** this review,we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver *** lack of high-quality studies and evidence is a major obstacle in further treatment *** insights into the pathogenesis of not only liver injury,but also liver regeneration processes are mandatory for the development of new treatment options.A reliable experimental model of the pathogenesis of AH and processes involved in liver recovery is still missing,and data obtained from animal studies are essential for future research.

关键词： Severe alcoholic hepatitis Alcohol-related liver disease Treatment Liver regeneration Granulocyte colony-stimulating factor Stem cell transplantation

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Post-transplant diabetes mellitus and preexisting liver disease-a bidirectional relationship affecting treatment and management

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World Journal of Gastroenterology 2020年第21期26卷 2740-2757页

作者： Maja Cigrovski Berkovic lucija virovic-jukic Ines Bilic-Curcic Anna Mrzljak Department of Kinesiological Anthropology and Methodology Faculty of KinesiologyUniversity of ZagrebZagreb 10000Croatia Clinical Hospital Dubrava Zagreb 10000Croatia Department of Pharmacology Faculty of MedicineUniversity of J.J.Strossmayer OsijekOsijek 31000Croatia School of Medicine University of ZagrebZagreb 10000Croatia Department of Medicine Division of Gastroenterology and HepatologySisters of Charity University HospitalZagreb 10000Croatia

Liver cirrhosis and diabetes mellitus(DM)are both common conditions with significant socioeconomic burden and impact on morbidity and mortality.A bidirectional relationship exists between DM and liver cirrhosis regarding both etiology and disease-related *** 2 DM(T2DM)is a wellrecognized risk factor for chronic liver disease and vice-versa,DM may develop as a complication of cirrhosis,irrespective of its *** transplantation(LT)represents an important treatment option for patients with end-stage liver disease due to non-alcoholic fatty liver disease(NAFLD),which represents a hepatic manifestation of metabolic syndrome and a common complication of *** metabolic risk factors including immunosuppressive drugs,can contribute to persistent or de novo development of DM and NAFLD after LT.T2DM,obesity,cardiovascular morbidities and renal impairment,frequently associated with metabolic syndrome and NAFLD,may have negative impact on short and long-term outcomes following *** treatment of DM in the context of chronic liver disease and post-transplant is challenging,but new emerging therapies such as glucagon-like peptide-1 receptor agonists(GLP-1RAs)and sodium–glucose cotransporter 2 inhibitors(SGLT2i)targeting multiple mechanisms in the shared pathophysiology of disorders such as oxidative stress and chronic inflammation are a promising tool in future patient management.

关键词： Diabetes mellitus Liver transplantation Non-alcoholic fatty liver disease Metabolic syndrome Insulin-resistance Glucagon-like peptide-1 receptor agonists Sodium–glucose cotransporter 2 inhibitors

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New Drugs on the Block—Emerging Treatments for Nonalcoholic Steatohepatitis

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Journal of Clinical and Translational Hepatology 2021年第1期9卷 51-59页

作者： Sanja Stojsavljevic-Shapeski Marko Duvnjak lucija virovic-jukic Davor Hrabar Lea Smircic Duvnjak Department of Gastroenterology and Hepatology Clinical Hospital Center Sestre MilosrdniceZagrebCroatia Polyclinic Duvnjak ZagrebCroatia University of Applied Health Science ZagrebCroatia School of Medicine University of ZagrebZagrebCroatia Vuk Vrhovac University Clinic-UH Merkur ZagrebCroatia

Patients with nonalcoholic steatohepatitis(NASH)are at higher risk of progression to advanced stages of fibrosis,cirrhosis,hepatocellular carcinoma and other end-stage liver disease *** addressing treatment of NASH,we have limited approved options,and the mainstay of therapy is lifestyle *** research and revelation in the field of pathogenesis of NASH has offered new possibilities of treatment and emerging new drugs that are being tested currently in numerous preclinical and clinical *** drugs target almost all steps in the pathogenesis of NASH to improve insulin sensitivity,glucose and lipid metabolism,to inhibit de novo lipogenesis and delivery of lipids to the liver,and to influence apoptosis,inflammation and *** NASH is a multifactorial disease,in the future we could identify the predominating pathological mechanism and,by choosing the most appropriate specific medication,tailor the treatment for every patient individually.

关键词： Fatty liver Steatohepatitis Nonalcoholic fatty liver disease Treatment

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Shifting perspectives-interplay between non-alcoholic fatty liver disease and insulin resistance in lean individuals

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World Journal of Hepatology 2021年第1期13卷 80-93页

作者： Ines Bilic-Curcic Maja Cigrovski Berkovic lucija virovic-jukic Anna Mrzljak Department of Pharmacology Faculty of MedicineUniversity of J.J.Strossmayer OsijekOsijek 31000Croatia Clinical Hospital Center Osijek Osijek 31000Croatia Department of Kinesiological Anthropology and Methodology Faculty of KinesiologyUniversity of ZagrebZagreb 10000Croatia Clinical Hospital Dubrava Zagreb 10000Croatia Department of Medicine Division of Gastroenterology and HepatologySisters of Charity University HospitalZagreb 10000Croatia School of Medicine University of ZagrebZagreb 10000Croatia Department of Medicine Merkur University HospitalZagreb 10000Croatia

Non-alcoholic fatty liver disease(NAFLD)has become a significant public health burden affecting not only obese individuals but also people with normal *** opposed to previous beliefs,this particular subset of patients has an increased risk of all-cause mortality and worse outcomes than their obese *** development of NAFLD in lean subjects seems to be interconnected with metabolic phenotype,precisely visceral fat tissue,sarcopenia,and insulin ***,we summarize available data focusing on the co-dependent relationship between metabolic phenotype,insulin resistance,and development of NAFLD in lean individuals,suggesting more appropriate tools for measuring body fat distribution for the screening of patients at risk.

关键词： Non-alcoholic fatty liver disease Metabolic phenotype Lean individuals Insulin resistance Visceral fat tissue Sarcopenia

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Obesity Paradox in Chronic Liver Diseases:Product of Bias or a Real Thing?

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Journal of Clinical and Translational Hepatology 2019年第3期7卷 275-279页

作者： Ines Bilic Curcic Maja Cigrovski Berkovic lucija Kuna Hrvoje Roguljic Robert Smolic Silvija Canecki Varzic lucija virovic jukic Martina Smolic Department of Pharmacology Faculty of MedicineJ.J.Strossmayer University of OsijekOsijekCroatia Department of Diabetes Endocrinology and Metabolism DisordersOsijek University Hospital CentreFaculty of MedicineJosip Juraj Strossmayer University of OsijekOsijekCroatia Department for Endocrinology Diabetes and Metabolism University Hospital Center"Sestre Milosrdnice"ZagrebCroatia Department of Pharmacology and Biochemistry Faculty of Dental Medicine and HealthJ.J.Strossmayer University of OsijekOsijekCroatia Department for Cardiovascular Disease Osijek University HospitalOsijekCroatia Department of Gastroenterology and Hepatology Osijek University Hospital CentreFaculty of MedicineJosip Juraj Strossmayer University of OsijekOsijekCroatia Department of Pathophysiology Faculty of MedicineJosip Juraj Strossmayer University of OsijekOsijekCroatia Department of Internal Medicine Faculty of MedicineJosip Juraj Strossmayer University of OsijekOsijekCroatia Department of Gastroenterology and Hepatology Sisters of Mercy University HospitalUniversity of Zagreb School of MedicineZagrebCroatia Department of Pharmacology J.J.Stross-mayer University of Osijek Faculty of Medicine OsijekJ.Huttlera 4Osijek 31000Croatia

In recent years,evidence supporting the theory of obesity paradox has increased,showing that obese/overweight people with prevalent chronic diseases experience lower mortality compared with patients of normal *** far,evidence is most comprehensive in cardiovascular and chronic renal diseases;however,published studies are prone to many biases,enabling us to reach a definite *** data in chronic liver disease is scarce and *** is traditionally associated with nonalcoholic fatty liver disease and steatosis in viral hepatitis and as such one would not expect the obesity paradox to be a real possibility in liver ***,there seem to be new data indicating the opposite-the obesity paradox exists in severe and end-stage liver cirrhosis,which could be attributed to a better lean mass in patients with higher body mass index,meaning that sarcopenia,as one of the most important prognostic factors of survival,is less likely to be ***,the problem of various methodological problems addressing the association between body weight and mortality,which is present both in liver disease and other chronic diseases,are preventing us from attaining an unanimous ***,we should be aware that the obesity paradox might be true,especially in severe and end-stage *** suggests focusing our efforts toward preserving or building up fat-free mass and decreasing infiammatory activity responsible for catabolism and sarcopenia,and implying that the underlaying cause should be treated.

关键词： Obesity paradox Chronic liver disease NAFLD NASH Cirrhosis

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Expression of adipokine ghrelin and ghrelin receptor in human colorectal adenoma and correlation with the grade of dysplasia

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World Journal of Gastrointestinal Surgery 2021年第12期13卷 1708-1720页

作者： Sanja Stojsavljevic-Shapeski lucija virovic-jukic Davor Tomas Marko Duvnjak Vedran Tomasic Davor Hrabar Dominik Kralj Ivan Budimir Neven Barsic Neven Ljubicic Division of Gastroenterology Department of Internal Medicine«Sestre Milosrdnice»University Hospital CenterZagreb 10000Croatia Department of Internal Medicine School of MedicineUniversity of ZagrebZagreb 10000Croatia Ljudevit Jurak Department of Pathology «Sestre Milosrdnice»University Hospital CenterZagreb 10000Croatia Department of Pathology School of MedicineUniversity of ZagrebZagreb 10000Croatia

BACKGROUNDGhrelin is an adipokine that plays an important role in energy balance. Expressionof ghrelin and ghrelin receptor has been investigated in different tissues andtumors. Studies regarding expression of ghrelin and ghrelin receptor in colorectaltumors are scarce and no data on expression of ghrelin and its receptor incolorectal adenomas has been published. Ghrelin and ghrelin receptor werehighly expressed in colon carcinoma cells while expression was decreased in lessdifferentiated tumors, presuming that ghrelin might be important in early phasesof *** investigate the expression of ghrelin and ghrelin receptor in human colorectaladenomas and adjacent colorectal *** this prospective study (conducted from June 2015 until May 2019) we included92 patients (64 male and 28 female) who underwent polypectomy for colorectaladenomas in the Department of Gastroenterology and Hepatology, “Sestre milosrdnice” Clinical Hospital Center in Zagreb, Croatia. After endoscopicremoval of colorectal adenoma, an additional sample of colon mucosa in theproximity of the adenoma was collected for pathohistological analysis. Adenomaswere graded according to the stage of dysplasia, and ghrelin and ghrelin receptorexpression were determined immunohistochemically in both adenoma andadjacent colon tissue using the polyclonal antibody for ghrelin (ab150514,ABCAM Inc, Cambridge, United States) and ghrelin receptor (ab48285, ABCAMInc, Cambridge, United States). Categorical and nominal variables were describedthrough frequencies and proportions and the difference between specific groupswere analyzed with Fisher’s and Fisher-Freeman-Halton’s method ***'s rank correlation coefficient was determined for correlation ofexpression of ghrelin and ghrelin receptor in adenoma and adjacent colon tissuewith the grade of adenoma *** 92 patients with colorectal adenoma 43 had adenomas with high-gradedysplasia (46.7%). High expression of ghre

关键词： Ghrelin Ghrelin receptor Adipokines Colorectal adenoma Colorectal adenoma dysplasia Large intestine

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