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Are treatment options used for adult-onset type 2 diabetes mellitus(equally)available and effective for children and adolescents?

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World Journal of Diabetes 2024年第4期15卷 623-628页

作者： Nevena Krnic Vibor Sesa anna mrzljak Maja Cigrovski Berkovic Clinics for Pediatrics University Hospital Center ZagrebZagreb 10000Croatia Department of Gastroenterology and Hepatology University Hospital Centre ZagrebZagreb 10000Croatia University of Zagreb School of Medicine Zagreb 10000Croatia Department for Sport and Exercise Medicine University of Zagreb Faculty of KinesiologyZagreb 10000Croatia

Youth-onset type 2 diabetes mellitus(T2DM),influenced by an increase in obesity,is a rising problem worldwide.Pathophysiological mechanisms of this early-onset T2DM include both peripheral and hepatic insulin resistance,along with increa-sed hepatic fasting glucose production accompanied by inadequate first and second-phase insulin secretion.Moreover,the incretin effect is reduced.The initial presentation of type 2 diabetes can be dramatic and symptoms may overlap with those of type 1 diabetes mellitus.Therefore,immediate therapy should address hyperglycemia and associated metabolic derangements irrespective of ultimate diabetes type,while further therapy adjustments are prone to patients’pheno-type.New agents with proven glycemic and beyond glycemia benefits,such as Glucagon-like polypeptide 1 receptor agonists and Sodium-glucose cotransporter-2 inhibitors,used in the adult population of T2DM patients,might become increasingly important in the treatment armamentarium.Moreover,metabolic surgery is an option for markedly obese(body mass index>35 kg/m^(2))children and adolescents suffering from T2DM who have uncontrolled glycemia and/or serious comorbidities when lifestyle and pharmacologic interventions fail.In this mini-review,we will discuss the potential of treatment options considering new data available from randomized control trials,including individuals with adult-onset type diabetes mellitus.

关键词： Youth-onset type 2 diabetes mellitus Treatment Complications Glucose lowering agents Extra-glycemic benefit

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Metformin and pancreatic neuroendocrine tumors:A systematic review and meta-analysis

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World Journal of Gastroenterology 2024年第7期30卷 759-769页

作者： Maja Cigrovski Berkovic Alessandro Coppola Vibor Sesa anna mrzljak Quirino Lai Department for Sport and Exercise Medicine Faculty of Kinesiology University of ZagrebZagreb 10000Croatia Department of Surgery Sapienza University of RomeRome 00185Italy Department of Gastroenterology and Hepatology Liver Transplant CenterUniversity Hospital Centre ZagrebZagreb 10000Croatia Department of Medicine School of MedicineZagreb 10000Croatia General Surgery and Organ Transplantation Unit Department of SurgerySapienza University of RomeRome 00018Italy

BACKGROUND Most patients with advanced pancreatic neuroendocrine tumors(pNETs)die due to tumor progression.Therefore,identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant.In this perspective,metformin is emerging as a molecule of interest.Retrospective studies have described metformin,a widely used agent for the treatment of patients with type 2 diabetes mellitus(T2DM),to be effective in modulating different tumor-related events,including cancer incidence,recurrence and survival by inhibiting mTOR phosphorylation.This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.AIM To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and posttreatment outcomes of pNET.METHODS A systematic review of the published literature was undertaken,focusing on the role of T2DM and metformin in insurgence and prognosis of pNET,measured through outcomes of tumor-free survival(TFS),overall survival and progression free survival.RESULTS A total of 13 studies(5674 patients)were included in this review.Analysis of 809 pNET cases from five retrospective studies(low study heterogeneity with I^(2)=0%)confirms the correlation between T2DM and insurgence of pNET(OR=2.13,95%CI=1.56-4.55;P<0.001).The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients(hazard ratio=1.84,95%CI=0.78-2.90;P<0.001).The study heterogeneity was intermediate,with I^(2)=51%.A few studies limited the possibility of performing pooled analysis in the setting of metformin;therefore,results were heterogeneous,with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.CONCLUSION T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients.Unfortunately,a few studies wi

关键词： Pancreatic neuroendocrine tumors Type 2 diabetes mellitus Prognosis Treatment Metformin

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Immunology demystified: A guide for transplant hepatologists

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World Journal of Transplantation 2024年第1期14卷 48-61页

作者： Iva Kosuta Tomislav Kelava Ana Ostojic Vibor Sesa anna mrzljak Hrvoje Lalic Department of Intensive Care Medicine University Hospital Centre ZagrebZagreb 10000Croatia Department of Physiology School of MedicineUniveristy of ZagrebZagreb 10000Croatia Laboratory for Molecular Immunology Croatian Institute for Brain ResearchZagreb 10000Croatia Department of Gastroenterology and Hepatology Liver Transplant CenterUniversity Hospital Centre ZagrebZagreb 10000Croatia Department of Medicine School of MedicineUniversity of ZagrebZagreb 10000Croatia Department of Physiology University of Zagreb School of MedicineZagreb 10000Croatia Laboratory for Cell Biology Croatian Institute for Brain ResearchUniversity of Zagreb School of MedicineZagreb 10000Croatia Department of Laboratory Immunology Clinical Department of Laboratory DiagnosticsUniversity Hospital Center ZagrebZagreb 10000Croatia

Liver transplantation has become standard practice for treating end-stage liver disease.The success of the procedure relies on effective immunosuppressive medications to control the host's immune response.Despite the liver's inherent capacity to foster tolerance,the early post-transplant period is marked by significant immune reactivity.To ensure favorable outcomes,it is imperative to identify and manage various rejection types,encompassing T-cell-mediated,antibody-mediated,and chronic rejection.However,the approach to prescribing immunosuppressants relies heavily on clinical judgment rather than evidencebased criteria.Given that the majority of patients will require lifelong immunosuppression as the mechanisms underlying operational tolerance are still being investigated,healthcare providers must possess an understanding of immune responses,rejection mechanisms,and the pathways targeted by immunosuppressive drugs.This knowledge enables customization of treatments and improved patient care,even though a consensus on an optimal immunosuppressive regimen remains elusive.

关键词： Liver transplantation Allograft rejection Operational immune tolerance Immune reaction Immunosuppression

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Acute pancreatitis as a complication of acute COVID-19 in kidney transplant recipients

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World Journal of Clinical Cases 2024年第6期12卷 1104-1110页

作者： Nikolina Basic-Jukic Ivana Juric Lea Katalinic Vesna Furic-Cunko Vibor Sesa anna mrzljak Department of Nephrology Arterial HypertensionDialysis and TransplantationUniversity Hospital Centre ZagrebZagreb 10000Croatia Department of Medicine School of MedicineZagreb 10000Croatia Department of Gastroenterology and Hepatology University Hospital Centre ZagrebZagreb 10000Croatia

BACKGROUND Acute pancreatitis is a rare extrapulmonary manifestation of coronavirus disease 2019(COVID-19)but its full correlation with COVID-19 infection remains unknown.AIM To identify acute pancreatitis’occurrence,clinical presentation and outcomes in a cohort of kidney transplant recipients with acute COVID-19.METHODS A retrospective observational single-centre cohort study from a transplant centre in Croatia for all adult renal transplant recipients with a functioning kidney allograft between March 2020 and August 2022 to record cases of acute pancreatitis during acute COVID-19.Data were obtained from hospital electronic medical records.Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection was proven by a positive SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction on the nasopharyngeal swab.RESULTS Four hundred and eight out of 1432(28.49%)patients who received a renal allograft developed COVID-19 disease.The analyzed cohort included 321 patients(57%males).One hundred and fifty patients(46.7%)received at least one dose of the anti-SARS-CoV-2 vaccine before the infection.One hundred twenty-five(39.1%)patients required hospitalization,141(44.1%)developed pneumonia and four patients(1.3%)required mechanical ventilation.Treatment included immunosuppression modification in 233 patients(77.1%)and remdesivir in 53 patients(16.6%),besides the other supportive measures.In the study cohort,only one transplant recipient(0.3%)developed acute pancreatitis during acute COVID-19,presenting with abdominal pain and significantly elevated pancreatic enzymes.She survived without complications with a stable kidney allograft function.CONCLUSION Although rare,acute pancreatitis may complicate the course of acute COVID-19 in kidney transplant recipients.The mechanism of injury to the pancreas and its correlation with the severity of the COVID-19 infection in kidney transplant recipients warrants further research.

关键词： Acute pancreatitis COVID-19 Kidney transplant Angiotensin-converting enzyme-2 receptor Immunosuppressive agents

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Lymphocytic choriomeningitis virus:An under-recognized congenital teratogen

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World Journal of Clinical Cases 2022年第25期10卷 8922-8931页

作者： Thomas Ferenc Mateja Vujica anna mrzljak Tatjana Vilibic-Cavlek Department of Radiology Merkur University HospitalZagreb 10000Croatia Department of Emergency Medicine Institute of Emergency Medicine of Krapina-Zagorje CountyKrapina 49000Croatia Department of Gastroenterology and Hepatology University Hospital Center ZagrebZagreb 10000Croatia School of Medicine University of ZagrebZagreb 10000Croatia Department of Virology Croatian National Institute of Public HealthZagreb 10000Croatia

BACKGROUND Lymphocytic choriomeningitis virus(LCMV)is a neglected rodent-borne arenavirus associated with transplacental transmission and fetal infection.AIM To summarize the epidemiological,clinical,and diagnostic features of reported patients with congenital LCMV infection.METHODS A literature search was conducted in PubMed,Medline,Google Scholar,and ResearchGate.The keywords used were‘congenital lymphocytic choriomeningitis virus,’and 48 studies were included.In addition,we conducted a relevant search by Reference Citation Analysis(RCA)(https://www.referencecitationan ***).RESULTS The results have shown 27 reports of congenital LCMV infection in 86 patients,with 52.73%of them being males.Patients presented with chorioretinitis(83.53%),hydrocephalus(54.12%),and psychomotor retardation or developmental delay(54.12%).Computed tomography and/or magnetic resonance imaging most often demonstrated ventriculomegaly(74.07%),periventricular calcifications(66.67%),and microcephaly(40%).Most mothers of congenitally infected infants were exposed to rodents during pregnancy,predominantly mice,with flu-like symptoms mainly occurring during the first two trimesters of gestation.Mortality in congenitally infected children was 16.47%.The diagnosis of congenital LCMV infection was confirmed serologically in most patients(86.67%).CONCLUSION LCMV is still an insufficiently recognized fetal teratogen that often leads to long-term neurologic sequelae.Clinicians need to be familiar with LCMV and its potential teratogenic effect and as well as to effectively differentiate LCMV from other TORCH(T:Toxoplasma gondii,O:Other pathogens,R:Rubella virus,C:Cytomegalovirus,H:Herpes simplex virus)pathogens.

关键词： Lymphocytic choriomeningitis virus Congenital infection Epidemiology Pregnancy TORCH

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Semaglutide might be a key for breaking the vicious cycle of metabolically associated fatty liver disease spectrum?

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World Journal of Clinical Cases 2022年第20期10卷 6759-6768页

作者： Maja Cigrovski Berkovic Tanja Rezic Ines Bilic-Curcic anna mrzljak Department of Endocrinology DiabetesMetabolism and Clinical PharmacologyClinical Hospital DubravaZagreb 10000Croatia Faculty of Kinesiology University of ZagrebZagreb 10000Croatia Department of Endocrinology and Diabetes Clinical Hospital DubravaZagreb 10000Croatia Department of Endocrinology and Diabetes University Hospital Centre OsijekOsijek 31000Croatia Department of Gastroenterology and Hepatology University Hospital Centre ZagrebZagreb 10000Croatia School of Medicine University of ZagrebZagreb 10000Croatia

Metabolically associated fatty liver disease(MAFLD)is a liver manifestation of metabolic syndrome potentially related to unfavorable hepatic and extrahepatic outcomes and progression to cirrhosis.Up to date,there are no approved pharmacotherapies for the treatment of MAFLD,so management focused on lifestyle interventions to encourage weight loss,and treatment of coexisting conditions is the only available option.Unfortunately,the aforementioned is often not potent enough to offer reversal or slow down hepatic inflammation and fibrosis.Glucagon-like peptide-1 receptor agonists have a favorable effect on glycemic management and weight loss of patients with type 2 diabetes mellitus and recently published data suggest their potential in MAFLD treatment.In addition,some of the agents have proven cardiovascular and renal benefits in dedicated cardiovascular outcome trials,making them an interesting therapeutic option.In this opinion review,we discuss the role of semaglutide in MAFLD.

关键词： Semaglutide Non-alcoholic fatty liver disease Glucagon-like peptide-1 receptor agonists Metabolically associated fatty liver disease

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Malignant insulinoma:Can we predict the long-term outcomes?

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World Journal of Clinical Cases 2022年第16期10卷 5124-5132页

作者： Maja Cigrovski Berkovic Monika Ulamec Sonja Marinovic Ivan Balen anna mrzljak Department of Endocrinology DiabetesMetabolism and Clinical PharmacologyClinical Hospital DubravaZagreb 10000Croatia Department of Kinesiological Anthropology and Methodology Faculty of KinesiologyUniversity of ZagrebZagreb 10000Croatia Department of Pathology and Cytology“Ljudevit Jurak” University Hospital Center“Sestre milosrdnice”Zagreb 10000Croatia Scientific Group for Research on Epigenetic Biomarkers and Department of Pathology School of MedicineUniversity of ZagrebZagreb 10000Croatia Laboratory for Personalized Medicine Division of Molecular MedicineRudjer Boskovic InstituteZagreb 10000Croatia Department of Gastroenterology and Endocrinology General Hospital“Dr.Josip Bencevic”Slavonski Brod 35000Croatia Department of Gastroenterology and Hepatology UHC ZagrebZagreb 10000Croatia School of Medicine University of ZagrebZagreb 10000Croatia

Insulinomas are the most frequent type of functional pancreatic neuroendocrine tumors with a variety of neuroglycopenic and autonomic symptoms and welldefined diagnostic criteria;however,prediction of their clinical behavior and early differentiation between benign and malignant lesions remain a challenge.The comparative studies between benign and malignant cases are limited,suggesting that short clinical history,early hypoglycemia during fasting,high proinsulin,insulin,and C-peptide concentrations raise suspicion of malignancy.Indeed,malignant tumors are larger with higher mitotic count and Ki-67 proliferative activity,but there are no accurate histological criteria to distinguish benign from malignant forms.Several signaling pathways have been suggested to affect the pathophysiology and behavior of insulinomas;however,our knowledge is limited,urging a further understanding of molecular genetics.Therefore,there is a need for the identification of reliable markers of metastatic disease that could also serve as therapeutic targets in patients with malignant insulinoma.This opinion review reflects on current gaps in diagnostic and clinical aspects related to the malignant behavior of insulinoma.

关键词： Pancreatic neuroendocrine tumor Malignant insulinoma Resection Liver Transplantation

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Prognostic role of metformin in diabetes mellitus type 2 patients with hepatocellular carcinoma:A systematic review and meta-analysis

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World Journal of Diabetes 2023年第8期14卷 1289-1300页

作者： Maja Cigrovski Berkovic Francesco Giovanardi anna mrzljak Quirino Lai Department of Kinesiological Anthropology and Methodology Faculty of KinesiologyUniversity of ZagrebZagreb 10000Croatia General Surgery and Organ Transplantation Unit Department of SurgerySapienza University of RomeRome 00018Italy Department of Gastroenterology and Hepatology University Hospital Center ZagrebZagreb 10000Croatia Department of Medicine School of MedicineZagreb 10000Croatia

BACKGROUND Hepatocellular carcinoma(HCC)is among the commonest malignancies associated with significant cancer-related death.The identification of chemopreventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing.Metformin,a first-line agent used in the treatment of type 2 diabetes mellitus(T2DM),has been associated with inhibition of HCC growth.AIM To determine whether metformin can prevent adverse events(i.e.,death,tumor progression,and recurrence)after any HCC treatment in T2DM patients.METHODS A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy.A search of the PubMed and Cochrane Central Register of Controlled Trials Databases was conducted.RESULTS A total of 13 studies(n=14886 patients)were included in this review.With regard to the risk of death,a decreased risk was reported in cases receiving metformin,although this decrease was not statistically significant[odds ratio(OR)=0.89,P=0.42].When only patients treated with curative strategies were considered,a more marked correlation between metformin and favorable cases was reported(OR=0.70,P=0.068).When analyzing palliative treatment,there was no statistical significance in terms of the correlation between metformin and favorable cases(OR=0.74,P=0.66).As for the risks of progressive disease and recurrence,no obvious correlation between metformin use and reduced risk was reported.When sub-analyses were performed for patients from different regions,the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin(OR=0.69,P=0.17),but the same was not seen in patients from Western countries(OR=1.19,P=0.31).CONCLUSION Metformin failed to show a marked impact in preventing adverse effects after HCC treatment.A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death,especially in patients from Eastern

关键词： Hepatocellular carcinoma Metformin Type 2 diabetes mellitus Death Recurrence Progression Treatment

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Prehabilitation of overweight and obese patients with dysglycemia awaiting bariatric surgery: Predicting the success of obesity treatment

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World Journal of Diabetes 2022年第12期13卷 1096-1105页

作者： Maja Cigrovski Berkovic Ines Bilic-Curcic anna mrzljak Silvija Canecki Varzic Vjekoslav Cigrovski Department of Endocrinology Diabetes and Clinical PharmacologyClinical Hospital DubravaZagreb 10000Croatia Faculty of Kinesiology University of ZagrebZagreb 10000Croatia Faculty of Medicine University of Osijek Osijek 31000Croatia Department of Endocrinology and Diabetes Clinical Hospital Centre OsijekOsijek 31000Croatia Department of Gastroenterology and Hepatology University Hospital Center ZagrebZagreb 10000Croatia School of Medicine University of ZagrebZagreb 10000Croatia

Bariatric surgery offers the best health results in overweight and obese patients but is not a risk and/or complication-free treatment.In cases with additional hyperglycemia,the burden of surgery can be even higher and alter both shortterm and long-term outcomes.Although bariatric surgery offers glycemic improvements and in the case of early onset diabetes disease remission,weight loss results are lower than for obese patients without diabetes.Different multimodal programs,usually including interventions related to patients’performance,nutritional and psychological status as well as currently available pharmacotherapy before the surgery itself might considerably improve the immediate and late postoperative course.However,there are still no clear guidelines addressing the prehabilitation of obese patients with dysglycemia undergoing bariatric surgery and therefore no unique protocols to improve patients’health.In this minireview,we summarize the current knowledge on prehabilitation before bariatric surgery procedures in patients with obesity and dysglycemia.

关键词： Bariatric surgery Obesity Dysgylcemia Diabetes outcome Prehabilitation

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Approach to persistent ascites after liver transplantation

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World Journal of Hepatology 2022年第9期14卷 1739-1746页

作者： Ana Ostojic Igor Petrovic Hrvoje Silovski Iva Kosuta Maja Sremac anna mrzljak Department of Gastroenterology and Hepatology University Hospital Center ZagrebZagreb 10000Croatia Department of Hepatobiliary Surgery and Transplantation University Hospital Center ZagrebZagreb 10000Croatia Department of Intensive Care Medicine University Hospital Center ZagrebZagreb 10000Croatia

Persistent ascites(PA)after liver transplantation(LT),commonly defined as ascites lasting more than 4 wk after LT,can be expected in up to 7%of patients.Despite being relatively rare,it is associated with worse clinical outcomes,including higher 1-year mortality.The cause of PA can be divided into vascular,hepatic,or extrahepatic.Vascular causes of PA include hepatic outflow and inflow obstructions,which are usually successfully treated.Regarding modifiable hepatic causes,recurrent hepatitis C and acute cellular rejection are the leading ones.Considering predictors for PA,the presence of ascites,refractory ascites,hepatorenal syndrome type 1,spontaneous bacterial peritonitis,hepatic encephalopathy,and prolonged ischemic time significantly influence the development of PA after LT.The initial approach to patients with PA should be to diagnose the treatable cause of PA.The stepwise approach in evaluating PA includes diagnostic paracentesis,ultrasound with Doppler,and an echocardiogram when a cardiac cause is suspected.Finally,a percutaneous or transjugular liver biopsy should be performed in cases where the diagnosis is unclear.PA of unknown cause should be treated with diuretics and paracentesis,while transjugular intrahepatic portosystemic shunt and splenic artery embolization are treatment methods in patients with refractory ascites after LT.

关键词： Liver transplantation Liver transplantation complications,Ascites Hepatic graft inflow obstructions Hepatic graft outflow obstructions Acute cellular rejection

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