Digestive and Liver Disease最新文献

{"title":"Incidence of clinical outcomes in patients with MASLD and long-term follow up: results from a single center cohort study","authors":"M. Marano,&nbsp;A. Armandi,&nbsp;G.P. Caviglia,&nbsp;C. Rosso,&nbsp;F. Amato,&nbsp;L. Vaira,&nbsp;K. Gjini,&nbsp;M. Guariglia,&nbsp;E. Dileo,&nbsp;E. Bugianesi","doi":"10.1016/j.dld.2025.01.084","DOIUrl":"10.1016/j.dld.2025.01.084","url":null,"abstract":"<div><h3>Introduction</h3><div>The natural history of MASLD results from environmental and genetic factors, impacting hepatic and extrahepatic outcomes. This study aims to elucidate the incidence of clinical outcomes, and the impact of non-invasive tests (NITs) and genetic factors.</div></div><div><h3>Materials and methods</h3><div>A retrospective study was conducted on patients undergoing vibration-controlled transient elastography (VCTE) for liver stiffness measurement (LSM), with at least 6 months follow-up. Other etiologies than MASLD, previous decompensation or hepatocarcinoma (HCC) were excluded. Significant liver fibrosis was defined by LSM≥8 Kpa, clinically significant portal hypertension (CSPH) by LSM≥25 Kpa. Primary endpoints included incidence of major adverse liver outcomes (MALOs): cirrhosis, liver decompensation (ascites, encephalopathy, variceal bleeding), HCC and liver transplant.</div></div><div><h3>Results</h3><div>504 patients were selected (61.7% males, median age 59 years [IQR 50.0-67.0]), with a median follow-up of 45.5 months [9.5-94.5]. Median LSM was 6.4 Kpa [5.0-9.0], 21% had PNPLA3 GG. Overall, 11.3% experienced MALOs (33.3% liver decompensation), 2.6% died (46.2% liver-related events). Significant fibrosis increased MALOs incidence (log rank p&lt;0.0001, HR14.4, 95%CI 5.5-13.3). CSPH raised liver decompensation occurrence (p=0.007, HR 6.1, 95%CI 3.3-22.4). Type 2 diabetes (T2D) and PNPLA3 GG increased MALOs incidence (p&lt;0.001, HR 3.8, 95%CI 2.03-6.2; p=0.004, HR 2.3, 95%CI 1.38-5.61). Obese/overweight patients had higher MALOs incidence than lean individuals (p=0.008, HR 2.67, 95% Cl 1.31-3.94). Multivariable Cox regression analysis showed that significant fibrosis by LSM was independently associated with MALOs (aHR 18.5, p&lt;0.0001, 95%Cl 5.65-60.7).</div></div><div><h3>Conclusions</h3><div>Overweight/obesity and T2D increase incidence of MALOs. LSM by VCTE and PNPLA3 genotyping are useful tools for risk stratification.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Page S45"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Portal Vein Recanalization-Transjugular Intrahepatic Portosystemic Shunt (PVR-TIPS) in patients with anatomical portal contraindication to liver transplantation: feasibility and clinical implication","authors":"C. Becchetti ,&nbsp;G. Perricone ,&nbsp;E. Motto ,&nbsp;F. Bolis ,&nbsp;F. Barbosa ,&nbsp;A. Alfonsi ,&nbsp;F. Morelli ,&nbsp;L. Centonze ,&nbsp;R. De Carlis ,&nbsp;E. Roselli ,&nbsp;A. Vanzulli ,&nbsp;G. Monti ,&nbsp;L.S. Belli ,&nbsp;A. Airoldi ,&nbsp;L. De Carlis ,&nbsp;A. Lauterio ,&nbsp;Marco Solcia","doi":"10.1016/j.dld.2025.01.090","DOIUrl":"10.1016/j.dld.2025.01.090","url":null,"abstract":"<div><h3>Introduction</h3><div>Portal vein thrombosis (PVT) may represent a relative contraindication to liver transplantation (LT). Transjugular intrahepatic portosystemic shunt (TIPS), a procedure intended to treat complications of portal hypertension, may allow portal vein (PV) recanalization (PVR).</div></div><div><h3>Aim</h3><div>We describe our single-center experience with PVR-TIPS in patients who are clinically candidates for LT but contraindicated because of PV anatomy.</div></div><div><h3>Methods</h3><div>We included consecutive patients who underwent PVT-TIPS at our center from February 2014 to May 2023. Patients with previous LT or vascular liver disease were excluded. Clinical variables at TIPS placement and LT were collected.</div></div><div><h3>Results</h3><div>We found 25 patients (19 males [76%], mean age 56 years [IQR 51-62]) in whom PVR-TIPS was offered for considering LT otherwise contraindicated because of PV anatomy. Twelve (48%) patients showed main PV thrombosis (PVT), 8 (32%) had cavernoma and 5 (20%) had PV with very small diameter. The main indication for LT was hepatocellular carcinoma (HCC) (10 patients, 40%), with 8 patients (32%) having active HCC at the time of PVR-TIPS. PVR-TIPS was successfully achieved in all but one patient. Concurrently, 9 patients (38%) underwent endovascular closure of porto-systemic shunts. All patients were listed post-PVR-TIPS with MELD at listing higher than pre-PVR-TIPS MELD (16±3 vs. 21±6, p&lt;0.001). Overall, 3 patients (12%) were delisted due to improvement in clinical status, 2 (8%) died on the waiting list, 14 (56%) underwent LT, while 5 (21%) are still on WL. LT was technically feasible with standard PV anastomosis. One patient died 141 days after LT due to endocarditis, while another was successfully retransplanted due to primary graft dysfunction.</div></div><div><h3>Conclusions</h3><div>PVR-TIPS may be a strategy to allow LT in patients otherwise excluded due to PV anatomy. It requires a high level of technical expertise and is often associated with a deterioration of liver function.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Pages S47-S48"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of the ERG1 potassium channel in cholangiocarcinoma cell biology","authors":"G. Alla Viligiardi,&nbsp;J. Iorio,&nbsp;M. Pastore,&nbsp;C. Duranti,&nbsp;R. Colasurdo,&nbsp;C. Capitani,&nbsp;T. Lottini,&nbsp;A. Arcangeli,&nbsp;C. Raggi,&nbsp;F. Marra","doi":"10.1016/j.dld.2025.01.015","DOIUrl":"10.1016/j.dld.2025.01.015","url":null,"abstract":"<div><h3>Background and Aim</h3><div>Due to the lack of proper biomarkers and potentially effective treatments, the management of cholangiocarcinoma (CCA) is still challenging. In this view, ion channels have been proven to be novel biomarkers as well as new targets for cancer therapy, due to their easy druggability. The voltage-gated K+ channel hERG1 exert pleiotropic effects in cancer cells. Thus, this study explored the influence of hERG1 in intrahepatic CCA (iCCA) susceptibility.</div></div><div><h3>Methods</h3><div>Validation of h<em>ERG1</em> in iCCA tissues was performed in TCGA database. In vitro experiments were assessed to estimate the impact of h<em>ERG1 inhibition</em> on cell function in iCCA cell lines (HUCCT1, CCLP1, CCA4).</div></div><div><h3>Results</h3><div>Significant difference in h<em>ERG1</em> gene expression was observed between iCCA and normal tissue samples. Similarly, iCCA cell lines significantly showed high protein content of hERG1 compared to normal cholangiocytes (NHC3).</div><div>Treatment with E4031, a selective hERG1 inhibitor as well genetic depletion (siRNA), showed, albeit limited impact of cell growth, a substantial reduction of invasive capability of iCCA cells. Moreover, immunoprecipitation assay and immunofluorescence revealed the formation of an active macromolecular complex with β1 integrin responsible for VEGF-A activation through the phosphorylation of AKT signaling.</div><div>Furthermore, treatment with the bispecific antibody (scDb: single-chain Diabody) that binds the hERG1-β1 complex, negatively impacted invasiveness of iCCA cells as well as expression of epithelial to mesenchymal genes. Importantly in vitro co-treatment with scDb and cisplatin-gemcitabine, significantly reduced growth of iCCA cells.</div></div><div><h3>Conclusions</h3><div>This study suggests that hERG1 may play a critical role in the initiation and progression of intrahepatic CCA, highlighting its potential as a therapeutic target.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Page S8"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of AMPK by a novel complex I modulator (CIM) reduces lipid accumulation and mitigates fibrosis in an in vivo model of MASLD","authors":"F. Protopapa ,&nbsp;A. Ferrigno ,&nbsp;M. Trucchi ,&nbsp;S. Lotti ,&nbsp;M. Vairetti ,&nbsp;A.C. Croce ,&nbsp;P. Sun ,&nbsp;S.G. Kauschke ,&nbsp;L.G. Di Pasqua","doi":"10.1016/j.dld.2025.01.075","DOIUrl":"10.1016/j.dld.2025.01.075","url":null,"abstract":"<div><h3>Introduction</h3><div>Mitochondrial complex I dysfunction is linked to lipid accumulation and excessive ROS production, contributing to MASLD progression. Metformin, a known complex I inhibitor, promotes lipolysis and β-oxidation <em>via</em> AMP-activated protein kinase (AMPK), a key regulator of lipid metabolism. This study aims to assess whether a novel complex I modulator (CIM) regulates lipid metabolism and hepatic fibrosis with a similar mechanism.</div></div><div><h3>Materials and Methods</h3><div>male Wistar rats, fed with a Methionine and Choline deficient (MCD) diet or Control diet for 6 weeks, were orally administered with complex I modulator (CIM, 10mg/Kg/day) or vehicle for the last 3 weeks. ATP content, NAD(P)H bound/free ratio, lipid accumulation, collagen deposition, protein and mRNA expression of key lipid and fibrosis markers were analyzed.</div></div><div><h3>Results</h3><div>CIM administration significantly reduced intrahepatic lipid content in MCD-fed rats, compared with untreated ones. Histological analysis revealed a significant reduction in lipid droplets in both CIM-treated groups, compared with untreated ones. ATP and NAD(P)H bound/free ratio decreased in CIM-treated controls, <em>versus</em> vehicle-treated rats. Activated AMPK increased in both CIM-treated groups, but the effect was significant only in control diet rats. Nuclear PPAR-a levels significantly rose in CIM-treated MCD-fed rats, relative to the untreated ones, while its cytoplasmic levels were significantly reduced in the same samples. CIM administration significantly decreased mRNA expression of <em>Srebp1c</em> and its target genes <em>Acaca</em> and <em>Fasn</em> in CIM-treated controls, with a similar trend observed in SREBP1c and mTOR protein levels. CIM-treated rats also showed a significant reduction in collagen deposition in both control rats and rats fed with MCD diet, along with a significant decrease in a-SMA protein expression in CIM-treated MCD rats. The same trend, although not significant, was observed for fibronectin protein expression.</div></div><div><h3>Conclusions</h3><div>CIM appears to be a promising strategy to improve liver lipids metabolism and is beneficial to hepatic steatosis and fibrosis.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Pages S39-S40"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncostatin M modulates the biology of cholangiocarcinoma cells and the tumor microenvironment","authors":"N. Porro ,&nbsp;J. Nurcis ,&nbsp;S. De Siervi ,&nbsp;M. Cadamuro ,&nbsp;C. Turato ,&nbsp;S. Mantovani ,&nbsp;B. Oliviero ,&nbsp;L. Fabris ,&nbsp;M. Mondelli ,&nbsp;F. Marra ,&nbsp;M. Parola ,&nbsp;Al. Caligiuri ,&nbsp;M. Pastore ,&nbsp;S. Cannito ,&nbsp;A. Gentilini","doi":"10.1016/j.dld.2025.01.031","DOIUrl":"10.1016/j.dld.2025.01.031","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Cholangiocarcinoma (CCA) is a highly aggressive tumor characterized by high resistance to chemotherapy and poor prognosis. Increasing evidence highlights that oncostatin M (OSM) regulates the tumor microenvironment (TME) and orchestrates the crosstalk between cancer and stromal cells. This project aims at elucidating the involvement of this factor and its receptor in iCCA progression, as well as in tumor-stroma interaction.</div></div><div><h3>Method</h3><div>Expression of OSM and its receptor was analysed in patients with iCCA by immunohistochemistry or RT-PCR. Two human iCCA cell lines (HuCCT-1 and CCLP-1) and two type of cultured stromal cells have been used in this study. Cell migration and invasiveness of iCCA cells has been evaluated by performing chemotaxis and invasion assays. Knockdown of OSMR and gp130 was carried out with specific siRNA in iCCA cells.</div></div><div><h3>Results</h3><div>iCCA cells expressed both OSM receptors and OSM at protein levels. In human CCA specimens, OSM was expressed at higher levels in cancer cells and in the tumor microenvironment with respect to peritumoral tissue. In addition, OSMR mRNA levels were higher in CCA. Exposure of iCCA to OSM induced a dose-dependent increase in cell migration and invasion. These effects were mediated by cytoskeletal rearrangement (increased expression of p-FAK, p-paxillin and p-MLC2), and inducing EMT. OSM also upregulated cancer-associated pathways including c-Myc, G6PD, p-Rb, and p-Akt The ability of OSM to induce iCCA cell migration and invasion was reduced after knockdown of the OSMR or of gp130, or treatment with ruxolitinib. Incubation of primary hepatic stellate cells, HSCs or cancer-associated fibroblasts, CAFs with conditioned medium collected from iCCA cells treated with OSM resulted in increased cell migration, suggesting a role in the formation of a dense fibrotic tumor microenvironment.</div></div><div><h3>Conclusions</h3><div>This study identifies the OSM/OSMR axis as a novel system potentially implicated in cholangiocarcinogenesis with modulation of the tumor microenvironment.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Page S18"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early hepatic decompensation is the main driver of mortality in patients with hepatocellular carcinoma treated with Atezolizumab plus Bevacizumab or Sorafenib","authors":"G. Cabibbo ,&nbsp;C. Celsa ,&nbsp;S. Battaglia ,&nbsp;M. Enea ,&nbsp;G. Di Maria ,&nbsp;A. Grova ,&nbsp;R. Ciccia ,&nbsp;G.F. Manfredi ,&nbsp;M. Iavarone ,&nbsp;A. Vogel ,&nbsp;A.G. Singal ,&nbsp;M. Reig ,&nbsp;D.J. Pinato ,&nbsp;C. Cammà","doi":"10.1016/j.dld.2025.01.042","DOIUrl":"10.1016/j.dld.2025.01.042","url":null,"abstract":"<div><h3>Introduction</h3><div>The prognosis of patients with unresectable hepatocellular carcinoma (uHCC) and compensated cirrhosis is influenced by cancer progression. Data on the incidence and the prognostic role of clinical hepatic decompensation following immune checkpoint inhibitor therapy are lacking.</div></div><div><h3>Aim</h3><div>We aimed to assess whether early clinical hepatic decompensation (CHD) within 3 months from commencement of systemic therapy affects overall survival (OS) of patients treated with Atezolizumab plus Bevacizumab or Sorafenib</div></div><div><h3>Materials and Methods</h3><div>Individual patient data from IMbrave150 trial were analyzed through Vivli platform. Cumulative incidence of CHD was assessed by competing risks analysis against HCC radiological progression. Early CHD and HCC radiological progression were assessed as predictors of OS by time-dependent Cox model.</div></div><div><h3>Results</h3><div>The 3- and 12-month rates of CHD were 7% and 12%, respectively, while the 3- and 12-month rates of HCC radiological progression were 23% and 52%. Albumin-bilirubin(ALBI)grade 2 (Sub-distribution hazard ratio[sHR] 1.79, 95%CI 1.01-3.19, p=0.049), INR(sHR 1.97, 95%CI 1.64-2.37, p&lt;0.001) and presence of neoplastic macrovascular invasion (sHR 2.01, 95%CI 1.14-3.54, p=0.020) were independently associated with higher risk of CHD. Early CHD(HR 7.56, 95%CI 4.47-12.8) and early HCC radiological progression(HR 5.92, 95%CI 4.03-8.69), as first events, were independently associated with higher mortality.</div></div><div><h3>Conclusions</h3><div>This study provides robust evidence that early CHD is associated with the highest risk of death in patients with uHCC undergoing systemic treatment. Within well-compensated participants, ALBI, INR and macrovascular invasion identify a population at higher risk of decompensation. Inclusion of clinical decompensation events in future prospective clinical trials may improve characterization of OS from systemic therapy of HCC.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Pages S21-S22"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Creatinine as a predictor of clinical events in Metabolic Dysfunction-Associated Steatotic Liver Disease","authors":"G. Di Betto ,&nbsp;A. Farina ,&nbsp;P. Palumbo ,&nbsp;B. Patrizi ,&nbsp;R. Righetti ,&nbsp;S. Ferrarini ,&nbsp;E. Corradini ,&nbsp;A. Pietrangelo ,&nbsp;E. Buzzetti","doi":"10.1016/j.dld.2025.01.072","DOIUrl":"10.1016/j.dld.2025.01.072","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic dysnfuction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease, and liver fibrosis is the primary predictor of liver-related events and mortality. Identifying patients at higher risk of progression is crucial for improving outcomes.</div></div><div><h3>Aim</h3><div>to characterize patients referred for hepatic steatosis to the Metabolic Clinic of AOU Policlinico of Modena with a minimum follow-up of 10 years and to assess the incidence and predictors of clinical events of interest.</div></div><div><h3>Material and Methods</h3><div>we prospectively enrolled all patients referred to the Metabolic Clinic for suspected NAFLD in the first years from its foundation (2011-2012). Retrospective data on cardiovascular events, liver-related events and mortality were collected. NITs for liver fibrosis were calculated and elastometric and histologic data were collected when available. Cox regression analysis was used to identify predictors of: 1) liver-related events, 2) cardiovascular events, 3) composite of death, hepatic decompensation, or cardiovascular events.</div></div><div><h3>Results</h3><div>the study population included 120 patients (33,3% females, mean age 53,32 ± 11,8 years). At baseline, 41 patients (37,3%) were obese (BMI of 29,02 ± 4,03), with T2DM, hypertension and dyslipidaemia prevalence of 14,2%, 26,7% and 76,7%, respectively (Figure 1). Over a mean follow-up of 11 years, 13 patients (10,8%) progressed to cirrhosis: 3 (5%) experienced hepatic decompensations, 3 developed HCC; 15 (12,5%) developed cardiovascular events, and 4 (3,3%) died.</div><div>Baseline Fib4 and APRI correlated with the composite outcome in univariate analysis, but not AGILE3. At the multivariate analysis, age, BMI and creatinine remained significant predictors (Figure2).</div></div><div><h3>Conclusion</h3><div>Creatinine levels may serve as an additional marker for identifying patients with MASLD who are at higher risk of clinical events, highlighting the possible, often subclinical, organ damage in this patient group.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Pages S37-S38"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomics maps the metabolic zonation of hepatocytes in MASLD I148M-PNPLA3 carriers","authors":"E. Paolini ,&nbsp;M. Longo ,&nbsp;M. Meroni ,&nbsp;A.L. Fracanzani ,&nbsp;P. Dongiovanni","doi":"10.1016/j.dld.2025.01.101","DOIUrl":"10.1016/j.dld.2025.01.101","url":null,"abstract":"<div><h3>Introduction</h3><div>The I148M <em>PNPLA3</em> polymorphism is the main genetic predictor of MASLD. Few data showed that I148M overexpression in hepatocytes correlated with metabolic switching and mitochondrial (mt)-dysfunction.</div></div><div><h3>Aims</h3><div>To deepen the impact of <em>PNPLA3</em> variation on mt-function by overexpressing I148M protein in HepG2 and Hep3B cells, to force or introduce the mutation, respectively; to dissect hepatocytes metabolic zonation in liver biopsies of MASLD patients, wild-type (WT) and homozygous for PNPLA3-I148M with similar disease severity (NAS=4), through spatial transcriptomic.</div></div><div><h3>Materials and Methods Results</h3><div>PNPLA3-I148M protein was upregulated in hepatoma cells by lentiviral transfection. Spatial transcriptomics was performed by Visium CytAssist (10X-Genomics). I148M-protein upregulation in hepatoma cells fostered lipid accumulation, thus increasing PGC1a to clear fat. Both I148M-overexpressed models showed lower OXPHOS capacity and ATP production alongside higher release of ROS and mtDNA fragments, corroborating the I148M-mediated mt-dysfunction. To explore the role of PNPLA3 I148M in hepatocytes zonation, we spatially mapped pericentral (PC) and periportal (PP) hepatocytes of WT and I148M MASLD-biopsies by using <em>CYP3A4/CYP2E1</em> and <em>HAL/SDS</em> genes as zonation markers, respectively. Among DEGs, we found increased lipogenesis (<em>SREPF1, DGAT2, ACACA, FABP1)</em> and mitobiogenesis (<em>PGC1a</em>), the latter as response to fat accumulation, in both WT-I148M-PP areas<em>.</em> However, WT-PP zones showed high expression of DEGs related to physiologic fusion-mitophagy (Mfn1, Mfn2, Opa1, BnipL, Bnip3), ðœ·-oxidation (PPAR<em>a)</em> and mt-respiration (SDHA, ATP5MF), that conversely were decreased in I148M-PP areas suggesting a mt-impairment. As concern pathways related to glycolysis, fatty acids metabolism, autophagy/mitophagy and PPAR/Wnt signaling, we observed an opposite trend between WT and I148M as they were enhanced in PC zones in the former and PP areas in the latter.</div></div><div><h3>Conclusion</h3><div>The <em>in vitro</em> I148M overexpression dampens mitochondrial respiration triggering oxidative stress. In MASLD patients, the I148M mutation leads to unbalanced PC-PP metabolic zonation providing new insights into its impact in the disease progression.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Page S55"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of a cohort of liver transplant patients for HBV and/or HBV/HDV related complications: results of a Campania multicenter study","authors":"G. Stornaiuolo ,&nbsp;L. Salmoni ,&nbsp;A. Russo ,&nbsp;D. Angrisani ,&nbsp;A. Santonicola ,&nbsp;G. Valente ,&nbsp;F. Longobardi ,&nbsp;F. Morisco ,&nbsp;M. Persico ,&nbsp;M. Stanzione ,&nbsp;C. Sagnelli ,&nbsp;M. Pisaturo ,&nbsp;N. Coppola","doi":"10.1016/j.dld.2025.01.079","DOIUrl":"10.1016/j.dld.2025.01.079","url":null,"abstract":"<div><h3>Introduction</h3><div>Liver transplantation is a life-saving treatment option for patients with complications related to HBV and/or HBV/HDV-related liver disease.</div></div><div><h3>Methods</h3><div>A multicenter retrospective study was conducted including 5 infectious disease or hepatology units in Campania. Patients receiving liver transplants for HBV and/or HBV/HDV-related complications were enrolled in post-transplant follow-up from 1 to a maximum of 20 years. The characteristics of patients with monoinfection were compared with those of HBV/HDV coinfected patients.</div></div><div><h3>Results</h3><div>We enrolled 233 patients, 109 of whom had confirmed HVB/HDV coinfection. Patients were predominantly male (76.4%), with a median age of 56 years, of whom 9.6% were HCVAb positive and 0.7% HIVAb positive; the median years of liver transplantation was 8 years. 64.5% of patients had a diagnosis of HCC at the time of transplantation. The comparison between the subjects transplanted for HBV and HBV/HDV did not show statistically significant epidemiological and demographic differences (table 1). During follow-up, 31.6% of patients had a clinical event: 6.4% liver-related and 27.8% not liver-related. Renal failure (20.9%) and cancer (12.85%) were the most frequent new-onset clinical events, with similar incidence between HBV patients and those with HBV/HDV coinfection (table 2). Patients in whom an adverse clinical event occurred were mostly men (79.7%, n.s.) (table 3). Only 4.2% of patients died during follow-up and of these only one death was related to a hepatic event (table 2). Comparing the characteristics (Table 4): they were all men (100% vs 75.3%; p = 0.122), they had been transplanted for longer (16 years vs 8; p = 0.059), 50% had been transplanted before 2010 and 50% of them were HDV coinfected (50%vs62.7%;p=0.674).</div></div><div><h3>Conclusions</h3><div>our study highlights a good outcome during follow-up and does not show different clinical evolution between liver transplant patients for HBV monoinfection and HBV/HDV coinfection.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Pages S41-S43"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The use of Controlled Attenuation Parameter for the assessment of treatment response in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease undergoing a lifestyle intervention program","authors":"L. Vaira ,&nbsp;A. Armandi ,&nbsp;C. Rosso ,&nbsp;G.P. Caviglia ,&nbsp;M. Marano ,&nbsp;F. Amato ,&nbsp;K. Gjini ,&nbsp;M. Guariglia ,&nbsp;E. Dileo ,&nbsp;I. Goitre ,&nbsp;D. Ribaldone ,&nbsp;S. Bo ,&nbsp;E. Bugianesi","doi":"10.1016/j.dld.2025.01.082","DOIUrl":"10.1016/j.dld.2025.01.082","url":null,"abstract":"<div><h3>Introduction</h3><div>Non-invasive biomarkers for the assessment of treatment response are highly needed in the clinical setting for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).</div></div><div><h3>Aim</h3><div>This study evaluates the role of Controlled Attenuation Parameter (CAP) by Vibration-Controlled Transient Elastography and PNPLA3 gene variants for the assessment of weight loss and BMI reduction in MASLD patients undergoing a 6-month dietary intervention.</div></div><div><h3>Materials and Methods</h3><div>94 MASLD patients were randomly assigned to 3 arms: Mediterranean Diet (MD), Low-Charb Diet (LCD), and Control Diet (CD). Inclusion criteria were BMI 26-35 kg/m², CAP≥248 dB/m, Liver Stiffness Measurement (LSM)&lt;12 kPa. Primary endpoints was ≥7% weight loss. Clinical/biochemical parameters and VCTE were assessment at baseline and after 6 months.</div></div><div><h3>Results</h3><div>Median age was 50.5 [IQR 43.0-61.0] years and 71.3% was male. Type 2 diabetes (T2D) was present in 17% of cases and PNPLA3 GG was present in 19.1% of cases. After 6 months, 28.7% of patients achieved ≥7% weight loss, with the highest proportion in LCD group (36.2%). In all patients achieving weight loss, CAP significantly decreased (from median 294 to median 246 dB/m, p&lt;0.0001), as compared to CAP changes that were observed in those who did not achieve weight loss (inter-group p-value=0.001). Delta CAP values were higher in LCD group (p=0.040). A stepwise increase in the delta CAP values was observed across incremental weight loss categories (&lt;5%, 5-10%,&gt;10%) (p=0.02). In patients achieving≥7% weight loss, delta CAP values were higher in patients with CC/CG genotype (p=0.0004), as compared to GG carriers (p=0.79).</div></div><div><h3>Conclusions</h3><div>In patients with MASLD undergoing lifestyle intervention, weight loss≥7% was associated with significant decreases in CAP values. PNPLA3 genotyping may be useful for further patient stratification.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Page S44"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}