New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches 2.0

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 21422

Special Issue Editor

General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Interests: liver diseases; genetics; metabolism; molecular biology; NAFLD; NASH; insulin resistance; genetics; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The liver plays an essential role in all metabolic processes, acting as a hub that integrates hormone and nutrient stimuli, and catabolic responses. It has a peculiar structure and anatomical localization that preserve the networking with the entire digestive system. Alterations in hepatic homeostasis are particularly harmful; hence, the increasing number of patients affected represents a global concern.

The term liver diseases embraces an umbrella of hepatic disorders, including viral and toxic hepatitis, inherited and acquired cholestatic injuries, nonalcoholic fatty liver disease (NAFLD), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). These disorders are usually complex in their molecular pathogenesis, and multiple risk factors may intervene in these processes. Among them, genetics and epigenetic factors have a primary impact in their development. Likewise, liver disorders are usually related to extrahepatic comorbidities, such as cardiovascular and intestinal complications. Since the gold standard for their diagnosis is still invasive and no therapeutic consensus exists for their management, this Special Issue aims to focus on new horizons in the discovery of noninvasive biomarkers and novel perspectives in the definition of the precise molecular mechanisms that precipitate liver damage towards end-stage conditions.

Dr. Marica Meroni
Guest Editor

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Research

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16 pages, 4543 KiB  
Article
Exogenous Volatile Organic Compound (EVOC®) Breath Testing Maximizes Classification Performance for Subjects with Cirrhosis and Reveals Signs of Portal Hypertension
by Giuseppe Ferrandino, Federico Ricciardi, Antonio Murgia, Iris Banda, Menisha Manhota, Yusuf Ahmed, Kelly Sweeney, Louise Nicholson-Scott, Lucinda McConville, Olga Gandelman, Max Allsworth, Billy Boyle, Agnieszka Smolinska, Carmen A. Ginesta Frings, Jorge Contreras, Claudia Asenjo-Lobos, Viviana Barrientos, Nataly Clavo, Angela Novoa, Amy Riviotta, Melissa Jerez and Luis Méndezadd Show full author list remove Hide full author list
Biomedicines 2023, 11(11), 2957; https://doi.org/10.3390/biomedicines11112957 - 01 Nov 2023
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Abstract
Background: Cirrhosis detection in primary care relies on low-performing biomarkers. Consequently, up to 75% of subjects with cirrhosis receive their first diagnosis with decompensation when causal treatments are less effective at preserving liver function. We investigated an unprecedented approach to cirrhosis detection based [...] Read more.
Background: Cirrhosis detection in primary care relies on low-performing biomarkers. Consequently, up to 75% of subjects with cirrhosis receive their first diagnosis with decompensation when causal treatments are less effective at preserving liver function. We investigated an unprecedented approach to cirrhosis detection based on dynamic breath testing. Methods: We enrolled 29 subjects with cirrhosis (Child–Pugh A and B), and 29 controls. All subjects fasted overnight. Breath samples were taken using Breath Biopsy® before and at different time points after the administration of 100 mg limonene. Absolute limonene breath levels were measured using gas chromatography–mass spectrometry. Results: All subjects showed a >100-fold limonene spike in breath after administration compared to baseline. Limonene breath kinetics showed first-order decay in >90% of the participants, with higher bioavailability in the cirrhosis group. At the Youden index, baseline limonene levels showed classification performance with an area under the roc curve (AUROC) of 0.83 ± 0.012, sensitivity of 0.66 ± 0.09, and specificity of 0.83 ± 0.07. The best performing timepoint post-administration was 60 min, with an AUROC of 0.91, sensitivity of 0.83 ± 0.07, and specificity of 0.9 ± 0.06. In the cirrhosis group, limonene bioavailability showed a correlation with MELD and fibrosis indicators, and was associated with signs of portal hypertension. Conclusions: Dynamic limonene breath testing enhances diagnostic performance for cirrhosis compared to static testing. The correlation with disease severity suggests potential for monitoring therapeutic interventions. Given the non-invasive nature of breath collection, a dynamic limonene breath test could be implemented in primary care. Full article
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15 pages, 2331 KiB  
Article
Effect of Kinins on the Hepatic Oxidative Stress in Mice Treated with a Methionine-Choline Deficient Diet
by Mariana Silva Thomaz, Marcela Nascimento Sertorio, Marcos Leoni Gazarini, Daniel Araki Ribeiro, Luciana Pellegrini Pisani and Marcia Regina Nagaoka
Biomedicines 2023, 11(8), 2199; https://doi.org/10.3390/biomedicines11082199 - 04 Aug 2023
Cited by 1 | Viewed by 777
Abstract
Non-alcoholic fatty liver is the leading cause of hepatic disease worldwide and ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) due to cell injury, oxidative stress, and apoptosis. The kinins’ role in the liver has been studied in experimental fibrosis, partial hepatectomy, and [...] Read more.
Non-alcoholic fatty liver is the leading cause of hepatic disease worldwide and ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) due to cell injury, oxidative stress, and apoptosis. The kinins’ role in the liver has been studied in experimental fibrosis, partial hepatectomy, and ischemia-reperfusion and is related to cell death and regeneration. We investigated its role in experimental NASH induced by a methionine-choline deficient diet for 4 weeks. After that, liver perfusion was performed, and bradykinin (BK) or des-Arg9-BK was infused. Cell death was evaluated by cathepsin-B and caspase-3 activity and oxidative stress by catalase (CAT), glutathione S-transferase, and superoxide dismutase (SOD) activities, as well as malondialdehyde and carbonylated proteins. In control livers, DABK increased CAT activity, which was reversed by antagonist DALBK. In the NASH group, kinins tend to decrease antioxidant activity, with SOD activity being significantly reduced by BK and DABK. Malondialdehyde levels increased in all NASH groups, but carbonylated protein did not. DABK significantly decreased cathepsin-B in the NASH group, while caspase-3 was increased by BK in control animals. Our results suggest that B1R and/or B2R activation did not induce oxidative stress but affected the antioxidant system, reducing SOD in the NASH group. Full article
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8 pages, 447 KiB  
Communication
The Impact of Renal Function on Hepatic Encephalopathy Following TIPS Placement for Refractory Ascites
by Matthew Zhao, Sammy Saab, Chloe Craw and Edward Wolfgang Lee
Biomedicines 2023, 11(8), 2171; https://doi.org/10.3390/biomedicines11082171 - 02 Aug 2023
Cited by 2 | Viewed by 992
Abstract
Background: The impact of renal function on hepatic encephalopathy (HE) following transjugular intrahepatic portosystemic shunt (TIPS) placement for refractory ascites is poorly understood. We investigated the role of renal function on HE following TIPS placement. Methods: A retrospective study was performed for patients [...] Read more.
Background: The impact of renal function on hepatic encephalopathy (HE) following transjugular intrahepatic portosystemic shunt (TIPS) placement for refractory ascites is poorly understood. We investigated the role of renal function on HE following TIPS placement. Methods: A retrospective study was performed for patients undergoing TIPS for refractory ascites from 2007–2019. Patients were stratified by GFR at time of TIPS placement and by whether they were on hemodialysis (HD). Chronic kidney disease (CKD) stage 3 or higher was defined as pre-TIPS GFR < 60 for at least 3 months. Logistic regression analyses were used to identify the role of GFR and CKD at time of TIPS placement on HE within 60 days post TIPS placement. Results: Among 201 TIPS patients for refractory ascites (61% male; mean age 59.1), 78 (39%) patients were in CKD, and 16 (21%) were on HD. Mean GFR at time of TIPS placement was 62.7 ± 28.2 for all non-HD patients (n = 185). Compared with the GFR ≥ 90 group, GFR < 30 or HD (OR, 3.56; 95%CI, 1.19–10.7; p = 0.023) and CKD (OR, 2.52; 95%CI, 1.40–4.53; p = 0.002) at time of TIPS placement were significant predictors of post-TIPS placement HE within 60 days. GFRs between 30–60 and 60–90 were not significant predictors. Conclusions: In TIPS patients for recurrent ascites, patients with acutely impaired renal function or chronic renal dysfunction were at an increased risk for HE after TIPS. Full article
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14 pages, 1520 KiB  
Article
New Diagnostic and Prognostic Models for the Development of Alcoholic Cirrhosis Based on Genetic Predisposition and Alcohol History
by Monica Mischitelli, Alessandra Spagnoli, Aurelio Abbatecola, Claudia Codazzo, Marta Giacomelli, Simona Parisse, Rosellina Margherita Mancina, Claudia Rotondo, Fabio Attilia, Stefano Ginanni Corradini and Flaminia Ferri
Biomedicines 2023, 11(8), 2132; https://doi.org/10.3390/biomedicines11082132 - 28 Jul 2023
Viewed by 661
Abstract
Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 [...] Read more.
Liver cirrhosis development is a multifactorial process resulting from a combination of environmental and genetic factors. The aim of the study was to develop accurate non-invasive diagnostic and prognostic models for alcoholic cirrhosis. Consecutive subjects with at-risk alcohol intake were retrospectively enrolled (110 cirrhotic patients and 411 non-cirrhotics). At enrollment, the data about lifetime drinking history were collected and all patients were tested for Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, Transmembrane 6 Superfamily 2 (TM6SF2) rs58542926, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 variants. In cross-sectional analyses, models for the diagnosis of cirrhosis were developed using multivariate logistic regression. A predictive score for cirrhosis development over 24 years was built by evaluating time-dependent AUC curves. The best diagnostic accuracy was demonstrated by the model, which also includes daily alcohol consumption, duration of hazardous alcohol use, and genetic variants, with AUCs of 0.951 (95% CI 0.925–0.977) and 0.887 (95% CI 0.925–0.977) for cirrhosis and compensated cirrhosis, respectively. The predictive model for future cirrhosis development (AUC of 0.836 95% CI: 0.769–0.904) accounted for age at onset of at-risk alcohol consumption and the number of PNPLA3 and HSD17B13 variant alleles. We have developed accurate genetic and alcohol consumption models for the diagnosis of alcoholic cirrhosis and the prediction of its future risk. Full article
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14 pages, 1187 KiB  
Article
Decreased Platelet Aggregation in Patients with Decompensated Liver Cirrhosis and TIPS Implantation
by Asala Nassar, Jan Patrick Huber, Daniela Stallmann, Diana Sharipova, Muataz Ali Hamad, Michael Schultheiss, Robert Thimme, Daniel Duerschmied, Rüdiger Eberhard Scharf, Dominik Bettinger and Krystin Krauel
Biomedicines 2023, 11(7), 2057; https://doi.org/10.3390/biomedicines11072057 - 21 Jul 2023
Viewed by 1139
Abstract
Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an effective treatment of portal hypertension in patients with decompensated liver cirrhosis. However, some patients develop TIPS thrombosis with recurrence of portal hypertension. The role of platelets in TIPS thrombosis and the necessity of antiplatelet therapy [...] Read more.
Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an effective treatment of portal hypertension in patients with decompensated liver cirrhosis. However, some patients develop TIPS thrombosis with recurrence of portal hypertension. The role of platelets in TIPS thrombosis and the necessity of antiplatelet therapy is unclear. Therefore, we aimed to study platelet function in patients with liver cirrhosis prior to and after TIPS implantation. Platelet aggregation was tested in peripheral and portal-vein blood patient samples on the day (D) of TIPS implantation (D0), D4 and D30 following the procedure (platelet count above 100 × 103/µL, aspirin starting on D5) using whole-blood impedance aggregometry (WBIA) and light transmission aggregometry (LTA). In addition, surface platelet activation markers (P-selectin, activated GPIIb/IIIa) and platelet–neutrophil complexes (PNCs) were assessed by flow cytometry. Thrombin receptor activating peptide 6 (TRAP-6), adenosine diphosphate (ADP) and arachidonic acid (AA) were used as agonists. Healthy subjects were included as controls. Agonist-induced platelet aggregation was reduced (WBIA: TRAP-6 p < 0.01, ADP p < 0.01, AA p < 0.001; LTA: TRAP-6 p = 0.13, ADP p = 0.05, AA p < 0.01) in patients (D0, n = 13) compared with healthy subjects (n = 9). While surface activation markers at baseline were negligibly low, the percentage of PNCs was higher in patients than in controls (p < 0.05). ADP-induced P-selectin expression was increased (p < 0.001), whereas TRAP-6-induced GPIIb/IIIa activation was impaired (p < 0.001) in patients versus controls. PNC formation in response to agonists was not different between groups. Results did not differ between peripheral and portal-vein blood of patients (D0, n = 11) and did not change over time (D0, D4, D30) following TIPS implantation (n = 9). In summary, patients with decompensated liver cirrhosis display in vitro platelet aggregation defects in response to various agonists. Defective aggregation persists upon TIPS implantation. Therefore, we conclude that antiplatelet treatment to prevent TIPS thrombosis is questionable. Full article
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9 pages, 1905 KiB  
Article
Clinical Impact and Safety of Non-Target Punctures (NTP) during Portal Vein Access in TIPS Procedure
by Sasikorn Feinggumloon, Zachary Haber, Sammy Saab, Fady Kaldas, Navid Eghbalieh, Thanh T. Luong, Justin P. McWilliams and Edward Wolfgang Lee
Biomedicines 2023, 11(6), 1630; https://doi.org/10.3390/biomedicines11061630 - 03 Jun 2023
Viewed by 1241
Abstract
Background: Although non-target puncture (NPT)-related complications are well known to clinicians performing TIPS, there is no NTP-focused study to assess the true clinical sequalae of NTP-related complications. In this study, the aim was to evaluate the incidence, safety, clinical outcomes and complications related [...] Read more.
Background: Although non-target puncture (NPT)-related complications are well known to clinicians performing TIPS, there is no NTP-focused study to assess the true clinical sequalae of NTP-related complications. In this study, the aim was to evaluate the incidence, safety, clinical outcomes and complications related to NTPs during the portal access of TIPS procedures. Methods: A retrospective review of 369 TIPS procedures from October 2007 to September 2019 was performed. We identified inadvertent NTPs, including biliary, hepatic artery, lymphatic and capsular punctures. Next, the medical records and images were reviewed and analyzed to assess the safety and clinical outcomes of these cohorts. Results: A total of 71 NTPs were identified in 56 patients (15.18% of 369 patients). Of 369 TIPS patients, there were (1) 28 biliary punctures (7.6%), (2) 16 extracapsular punctures (4.3%), (3) 15 lymphatic punctures (4.1%) and (4) 12 hepatic artery punctures (3.3%). The overall complication rate was 2.2% (8/369). Based on the Clavien–Dindo classification, three patients (0.8%) had a minor complication. In addition, five patients (1.4%) experienced grade II–V major complications, such as symptomatic hemoperitoneum, arterio-biliary fistula or hemorrhagic shock leading to death. Mortality (0.5%) was only caused by extracapsular puncture combined with other NTP. Conclusions: NTPs during the portal access of TIPS procedures are associated with low complication risk. However, when extracapsular punctures are combined with other NTPs, a more severe complication, including mortality, can occur. Nevertheless, all patients with NTP should be closely monitored at a higher level of care after TIPS placement. Full article
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14 pages, 1926 KiB  
Article
Hypocalcemia on Admission Is a Predictor of Disease Progression in COVID-19 Patients with Cirrhosis: A Multicenter Study in Hungary
by Bálint Drácz, Veronika Müller, István Takács, Krisztina Hagymási, Elek Dinya, Pál Miheller, Attila Szijártó and Klára Werling
Biomedicines 2023, 11(6), 1541; https://doi.org/10.3390/biomedicines11061541 - 26 May 2023
Cited by 1 | Viewed by 1859
Abstract
Hypocalcemia is a common condition in liver cirrhosis and is associated with the severity of SARS-CoV-2 infection. However, there is a lack of data demonstrating the prognostic value of hypocalcemia in COVID-19 patients with cirrhosis. This study aimed to evaluate the prognostic value [...] Read more.
Hypocalcemia is a common condition in liver cirrhosis and is associated with the severity of SARS-CoV-2 infection. However, there is a lack of data demonstrating the prognostic value of hypocalcemia in COVID-19 patients with cirrhosis. This study aimed to evaluate the prognostic value of hypocalcemia for COVID-19 severity, mortality and its associations with abnormal liver function parameters. We selected 451 COVID-19 patients in this retrospective study and compared the laboratory findings of 52 COVID-19 patients with cirrhosis to those of 399 COVID-19 patients without cirrhosis. Laboratory tests measuring albumin-corrected total serum calcium were performed on admission, and the levels were monitored during hospitalization. The total serum calcium levels were significantly lower in cirrhosis cases (2.16 mmol/L) compared to those without cirrhosis (2.32 mmol/L). Multivariate analysis showed that hypocalcemia in COVID-19 patients with cirrhosis was a significant predictor of in-hospital mortality, with an OR of 4.871 (p < 0.05; 95% CI 1.566–15.146). ROC analysis showed the AUC value of total serum calcium was 0.818 (95% CI 0.683–0.953, p < 0.05), with a sensitivity of 88.3% and a specificity of 75%. The total serum calcium levels showed a significant negative correlation with the Child–Turcette–Pugh score (r = −0.400, p < 0.05). Hypocalcemia on admission was a significant prognostic factor of disease progression in COVID-19 patients with cirrhosis. Full article
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15 pages, 2966 KiB  
Article
Transcriptional and Epigenetic Alterations in the Progression of Non-Alcoholic Fatty Liver Disease and Biomarkers Helping to Diagnose Non-Alcoholic Steatohepatitis
by Yalan Zhu, He Zhang, Pengjun Jiang, Chengxia Xie, Yao Luo and Jie Chen
Biomedicines 2023, 11(3), 970; https://doi.org/10.3390/biomedicines11030970 - 21 Mar 2023
Cited by 4 | Viewed by 1448
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions from simple steatosis (non-alcoholic fatty liver (NAFL)) to non-alcoholic steatohepatitis (NASH), and its global prevalence continues to rise. NASH, the progressive form of NAFLD, has higher risks of liver and non-liver related [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions from simple steatosis (non-alcoholic fatty liver (NAFL)) to non-alcoholic steatohepatitis (NASH), and its global prevalence continues to rise. NASH, the progressive form of NAFLD, has higher risks of liver and non-liver related adverse outcomes compared with those patients with NAFL alone. Therefore, the present study aimed to explore the mechanisms in the progression of NAFLD and to develop a model to diagnose NASH based on the transcriptome and epigenome. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) among the three groups (normal, NAFL, and NASH) were identified, and the functional analysis revealed that the development of NAFLD was primarily related to the oxidoreductase-related activity, PPAR signaling pathway, tight junction, and pathogenic Escherichia coli infection. The logistic regression (LR) model, consisting of ApoF, THOP1, and BICC1, outperformed the other five models. With the highest AUC (0.8819, 95%CI: 0.8128–0.9511) and a sensitivity of 97.87%, as well as a specificity of 64.71%, the LR model was determined as the diagnostic model, which can differentiate NASH from NAFL. In conclusion, several potential mechanisms were screened out based on the transcriptome and epigenome, and a diagnostic model was built to help patient stratification for NAFLD populations. Full article
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17 pages, 4844 KiB  
Article
Investigation of the Effect of Exendin-4 on Oleic Acid-Induced Steatosis in HepG2 Cells Using Fourier Transform Infrared Spectroscopy
by Olfa Khalifa, Kamal H. Mroue, Raghvendra Mall, Ehsan Ullah, Nayla S. Al-Akl and Abdelilah Arredouani
Biomedicines 2022, 10(10), 2652; https://doi.org/10.3390/biomedicines10102652 - 20 Oct 2022
Cited by 3 | Viewed by 1884
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver lesion that is untreatable with medications. Glucagon-like peptide-1 receptor (GLP-1R) agonists have recently emerged as a potential NAFLD pharmacotherapy. However, the molecular mechanisms underlying these drugs’ beneficial effects are not fully understood. Using Fourier [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a common liver lesion that is untreatable with medications. Glucagon-like peptide-1 receptor (GLP-1R) agonists have recently emerged as a potential NAFLD pharmacotherapy. However, the molecular mechanisms underlying these drugs’ beneficial effects are not fully understood. Using Fourier transform infrared (FTIR) spectroscopy, we sought to investigate the biochemical changes in a steatosis cell model treated or not with the GLP-1R agonist Exendin-4 (Ex-4). HepG2 cells were made steatotic with 400 µM of oleic acid and then treated with 200 nM Ex-4 in order to reduce lipid accumulation. We quantified steatosis using the Oil Red O staining method. We investigated the biochemical alterations induced by steatosis and Ex-4 treatment using Fourier transform infrared (FTIR) spectroscopy and chemometric analyses. Analysis of the Oil Red O staining showed that Ex-4 significantly reduces steatosis. This reduction was confirmed by FTIR analysis, as the phospholipid band (C=O) at 1740 cm−1 in Ex-4 treated cells is significantly decreased compared to steatotic cells. The principal component analysis score plots for both the lipid and protein regions showed that the untreated and Ex-4-treated samples, while still separated, are clustered close to each other, far from the steatotic cells. The biochemical and structural changes induced by OA-induced lipotoxicity are at least partially reversed upon Ex-4 treatment. FTIR and chemometric analyses revealed that Ex-4 significantly reduces OA-induced lipid accumulation, and Ex-4 also restored the lipid and protein biochemical alterations caused by lipotoxicity-induced oxidative stress. In combination with chemometric analyses, FTIR spectroscopy may offer new approaches for investigating the mechanisms underpinning NAFLD. Full article
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9 pages, 2381 KiB  
Article
Elevated Pre- and Postoperative ROTEM™ Clot Lysis Indices Indicate Reduced Clot Retraction and Increased Mortality in Patients Undergoing Liver Transplantation
by Matthias Hartmann, Benedikt Lorenz, Thorsten Brenner and Fuat H. Saner
Biomedicines 2022, 10(8), 1975; https://doi.org/10.3390/biomedicines10081975 - 15 Aug 2022
Cited by 5 | Viewed by 1272
Abstract
Background: The ROTEM™ clot lysis index, describing the decrease in firmness of a clot with time, predicts mortality in various settings. The variability of the clot lysis index in surgical procedures and the involved pathophysiological mechanisms are unknown. We therefore compared pre- and [...] Read more.
Background: The ROTEM™ clot lysis index, describing the decrease in firmness of a clot with time, predicts mortality in various settings. The variability of the clot lysis index in surgical procedures and the involved pathophysiological mechanisms are unknown. We therefore compared pre- and postoperative clot lysis indices in liver transplantation (LTX) procedures, determined the eventual association with mortality, and investigated the mechanisms underlying decreased clot lysis index using inhibitors of fibrinolysis and clot retraction, respectively. Methods: In this retrospective cohort study, data on pre- and post-transplant ROTEM™ findings as obtained with EXTEM (tissue factor activation), INTEM (intrinsic system activation), FIBTEM (extrinsic system activation and inhibition of clot retraction), APTEM (extrinsic system activation and fibrinolysis inhibition), conventional laboratory coagulation tests, blood loss, transfusion of blood products, and outcome were registered. Results: Pre-transplant clot lysis indices showed a broad distribution ranging from 75% to 99% independent of the activator used (EXTEM, INTEM). During the surgical procedure, median clot lysis index values markedly increased from 92% to 97% (EXTEM) and 93% to 98% (INTEM), respectively (p < 0.0001 each). Aprotinin had no effect on either pre- or postsurgical clot lysis indices. Inhibition of platelet clot retraction with cytochalasin D (FIBTEM) markedly increased the preoperative clot lysis index. High pre- and post-transplantation clot lysis indices were associated with increased mortality irrespective of the activator used (EXTEM, INTEM) and the inhibition of fibrinolysis (APTEM). Inhibition of clot retraction (FIBTEM) abolished the association of clot lysis index with mortality in both pre- and post-transplantation samples. Conclusion: Both pre- and postoperative ROTEM™ clot lysis indices predict mortality in patients following liver transplantation. Inhibitor experiments reveal that the clot lysis index is not an indicator of fibrinolysis, but indicates platelet clot retraction. The marked increase of clot lysis index during liver transplantation is caused by a decrease in clot retraction with eventual consequences for clot stability, retraction of wound margins, and reperfusion of vessels in case of thrombosis. Full article
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Review

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16 pages, 1191 KiB  
Review
The Potential Role of C-Reactive Protein in Metabolic-Dysfunction-Associated Fatty Liver Disease and Aging
by Zheng Ding, Yuqiu Wei, Jing Peng, Siyu Wang, Guixi Chen and Jiazeng Sun
Biomedicines 2023, 11(10), 2711; https://doi.org/10.3390/biomedicines11102711 - 05 Oct 2023
Viewed by 1362
Abstract
Nonalcoholic fatty liver disease (NAFLD), recently redefined as metabolic-dysfunction-associated fatty liver disease (MASLD), is liver-metabolism-associated steatohepatitis caused by nonalcoholic factors. NAFLD/MASLD is currently the most prevalent liver disease in the world, affecting one-fourth of the global population, and its prevalence increases with age. [...] Read more.
Nonalcoholic fatty liver disease (NAFLD), recently redefined as metabolic-dysfunction-associated fatty liver disease (MASLD), is liver-metabolism-associated steatohepatitis caused by nonalcoholic factors. NAFLD/MASLD is currently the most prevalent liver disease in the world, affecting one-fourth of the global population, and its prevalence increases with age. Current treatments are limited; one important reason hindering drug development is the insufficient understanding of the onset and pathogenesis of NAFLD/MASLD. C-reactive protein (CRP), a marker of inflammation, has been linked to NAFLD and aging in recent studies. As a conserved acute-phase protein, CRP is widely characterized for its host defense functions, but the link between CRP and NAFLD/MASLD remains unclear. Herein, we discuss the currently available evidence for the involvement of CRP in MASLD to identify areas where further research is needed. We hope this review can provide new insights into the development of aging-associated NAFLD biomarkers and suggest that modulation of CRP signaling is a potential therapeutic target. Full article
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24 pages, 1040 KiB  
Review
Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Strategies and Biomarkers Predicting Response and/or Resistance
by Filippo Pelizzaro, Fabio Farinati and Franco Trevisani
Biomedicines 2023, 11(4), 1020; https://doi.org/10.3390/biomedicines11041020 - 27 Mar 2023
Cited by 6 | Viewed by 2411
Abstract
In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with hepatocellular carcinoma (HCC). Following the positive results of the IMbrave150 trial, the combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) became the standard of care frontline [...] Read more.
In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with hepatocellular carcinoma (HCC). Following the positive results of the IMbrave150 trial, the combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) became the standard of care frontline treatment for patients with advanced stage HCC. Several other trials evaluated immunotherapy in HCC, demonstrating that ICIs-based regimens are currently the most effective treatment strategies and expanding the therapeutic possibilities. Despite the unprecedent rates of objective tumor response, not all patients benefit from treatment with ICIs. Therefore, in order to select the appropriate therapy as well as to correctly allocate medical resources and avoid unnecessary treatment-related toxicities, there is great interest in identifying the predictive biomarkers of response or resistance to immunotherapy-based regimens. Immune classes of HCC, genomic signatures, anti-drug antibodies, and patient-related factors (e.g., etiology of liver disease, gut microbiota diversity) have been associated to the response to ICIs, but none of the proposed biomarkers have been translated into clinical practice so far. Considering the crucial importance of this topic, in this review we aim to summarize the available data on tumor and clinical features associated with the response or resistance of HCC to immunotherapies. Full article
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28 pages, 1508 KiB  
Review
An Overview of Hepatocellular Carcinoma Surveillance Focusing on Non-Cirrhotic NAFLD Patients: A Challenge for Physicians
by Annalisa Cespiati, Felice Cinque, Marica Meroni, Rosa Lombardi, Paola Dongiovanni and Anna Ludovica Fracanzani
Biomedicines 2023, 11(2), 586; https://doi.org/10.3390/biomedicines11020586 - 16 Feb 2023
Cited by 2 | Viewed by 3790
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and it ranges from simple steatosis to hepatocellular carcinoma (HCC). HCC represents the first liver tumor and the third source of cancer death. In the next few years, the [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and it ranges from simple steatosis to hepatocellular carcinoma (HCC). HCC represents the first liver tumor and the third source of cancer death. In the next few years, the prevalence of NAFLD and consequently of HCC is estimated to increase, becoming a major public health problem. The NAFLD-HCC shows several differences compared to other causes of chronic liver disease (CLD), including the higher percentage of patients that develop HCC in the absence of liver cirrhosis. In HCC surveillance, the international guidelines suggest a six months abdominal ultrasound (US), with or without alpha-fetoprotein (AFP) evaluation, in patients with cirrhosis and in a subgroup of patients with chronic hepatitis B infection. However, this screening program reveals several limitations, especially in NAFLD patients. Thus, new biomarkers and scores have been proposed to overcome the limits of HCC surveillance. In this narrative review we aimed to explore the differences in the HCC features between NAFLD and non-NAFLD patients, and those between NAFLD-HCC developed in the cirrhotic and non-cirrhotic liver. Finally, we focused on the limits of tumor surveillance in NAFLD patients, and we explored the new biomarkers for the early diagnosis of HCC. Full article
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