Cirrhosis Research Articles

Hepatocellular CMPK2 promotes the development of metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), has limited pharmacological treatment options. Therefore, we aimed to identify novel therapeutic targets. The Gene Expression Omnibus (GEO) database and human liver tissues obtained from patients with MASH were used to identify differentially expressed genes in MASH. The functional role of cytidine/uridine monophosphate kinase 2 (CMPK2) was assessed in mice with hepatocyte-specific overexpression, conditional knockout mice, and several murine MASH models. CMPK2 inhibitors were discovered through surface plasmon resonance imaging coupled with indirect enzyme activity detection. CMPK2, a critical enzyme involved in mitochondrial DNA synthesis, exhibited significant upregulation in the livers of obese individuals with MASH and mice with diet-induced MASH. Hepatocyte-specific Cmpk2 deletion substantially mitigated liver injury, inflammation, and fibrosis in mice. Inhibition of CMPK2, either through genetic manipulation or pharmacological intervention with nordihydroguaiaretic acid (NDGA), suppressed NOD-like receptor family pyrin domain containing 3 (Nlrp3) inflammasome activation and subsequent hepatic pyroptosis. Furthermore, NDGA alleviated diet-induced metabolic disorders, inflammation, and fibrosis in vivo. These findings establish CMPK2 as a critical mediator in the progression from metabolic dysfunction-associated steatotic liver (MASL) to MASH and highlight its potential as a therapeutic target for metabolic diseases. CMPK2 exhibits upregulated in the MASH stage but not in the early stages of MASLD. Our study demonstrated that diet-induced MASH phenotypes, including liver injury, inflammation, and fibrosis were alleviated in hepatocyte-specific Cmpk2-knockout mice. These findings suggest that CMPK2 serve as a critical link in the progression of steatotic liver to steatohepatitis, offering novel mechanistic insights MASH development. Furthermore, this discovery identified CMPK2 as a promising target for the development of therapeutic drugs for MASH.

No association of ABO blood groups and Rh factor with primary liver cancer in cirrhotic patients: a single-center cross-sectional study

BackgroundPrimary liver cancer (PLC) is one of the most common cancers worldwide. ABO blood groups and rhesus (Rh) factor are inherited characteristics. Their association with the presence of PLC remains unclear in cirrhotic patients. Hence, the purpose of this cross-sectional study was to evaluate whether blood groups were risk factors for the presence of PLC in cirrhosis.MethodsPatients with liver cirrhosis who were consecutively admitted to the Department of Gastroenterology of the General Hospital of Northern Theater Command from 1 January 2010 to 30 June 2014 were retrospectively screened. Logistic regression analyses were performed to explore the association of ABO blood groups and Rh factor with PLC in cirrhotic patients. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated after adjusting for gender, age, family history of liver cirrhosis, HBV-DNA positivity, and etiology of cirrhosis. Subgroup analyses were performed according to the etiology of liver cirrhosis.ResultsOverall, 1,158 cirrhotic patients without PLC and 240 cirrhotic patients with PLC were included in the study. After adjusting for confounding factors, non-O (aOR = 0.763; 95%CI = 0.449–1.298, p = 0.319), A (aOR = 0.643; 95%CI = 0.332–1.246, p = 0.191), B (aOR = 0.835; 95%CI = 0.453–1.540, p = 0.564), AB (aOR = 0.888; 95%CI = 0.363–2.170, p = 0.795), and Rh (+) (aOR = 0.239; 95%CI = 0.036–1.571, p = 0.136) blood groups were not independently associated with PLC in cirrhotic patients. In the subgroup analysis of HBV-related cirrhotic patients, the proportion of A blood group was significantly lower in cirrhotic patients with PLC than in those without PLC (24.17% vs. 33.99%, p < 0.001); however, in HCV- and alcohol-related cirrhotic patients, the proportions of ABO blood groups and Rh factor were not significantly different between the two groups.ConclusionABO blood groups and Rh factor may not be associated with the presence of PLC in cirrhotic patients.

Changes in serum myostatin levels among patients with type C liver cirrhosis treated with direct‐acting antivirals

AbstractAimTo clarify whether direct‐acting antiviral treatment improves serum myostatin levels of patients with cirrhosis caused by hepatitis C virus.MethodsA total of 99 patients with type C liver cirrhosis were administered direct‐acting antiviral treatment. The median age was 73 years, and 58 patients were women. We measured the levels of serum myostatin, decorin, follistatin, and insulin‐like growth factor‐1, as well as the skeletal muscle mass index at baseline. We measured the sustained virological response at 48 weeks.ResultsSerum myostatin levels of the Child–Pugh class B or C group (n = 30) were significantly higher than those of the Child–Pugh class A group (n = 69) at baseline. The multivariate analysis indicated that the total bilirubin level and Mac‐2 binding protein glycosylation isomer level were independent factors associated with serum myostatin levels. Serum myostatin levels significantly decreased, whereas the skeletal muscle mass index and insulin‐like growth factor‐1 level were significantly increased at 48 weeks.ConclusionsDirect‐acting antiviral treatment decreased serum myostatin levels and may improve sarcopenia in patients with cirrhosis.

Clinical Applications of Artificial Intelligence (AI) in Human Cancer: Is It Time to Update the Diagnostic and Predictive Models in Managing Hepatocellular Carcinoma (HCC)?

In recent years, novel findings have progressively and promisingly supported the potential role of Artificial intelligence (AI) in transforming the management of various neoplasms, including hepatocellular carcinoma (HCC). HCC represents the most common primary liver cancer. Alarmingly, the HCC incidence is dramatically increasing worldwide due to the simultaneous “pandemic” spreading of metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD currently constitutes the leading cause of chronic hepatic damage (steatosis and steatohepatitis), fibrosis, and liver cirrhosis, configuring a scenario where an HCC onset has been reported even in the early disease stage. On the other hand, HCC represents a serious plague, significantly burdening the outcomes of chronic hepatitis B (HBV) and hepatitis C (HCV) virus-infected patients. Despite the recent progress in the management of this cancer, the overall prognosis for advanced-stage HCC patients continues to be poor, suggesting the absolute need to develop personalized healthcare strategies further. In this “cold war”, machine learning techniques and neural networks are emerging as weapons, able to identify the patterns and biomarkers that would have normally escaped human observation. Using advanced algorithms, AI can analyze large volumes of clinical data and medical images (including routinely obtained ultrasound data) with an elevated accuracy, facilitating early diagnosis, improving the performance of predictive models, and supporting the multidisciplinary (oncologist, gastroenterologist, surgeon, radiologist) team in opting for the best “tailored” individual treatment. Additionally, AI can significantly contribute to enhancing the effectiveness of metabolomics–radiomics-based models, promoting the identification of specific HCC-pathogenetic molecules as new targets for realizing novel therapeutic regimens. In the era of precision medicine, integrating AI into routine clinical practice appears as a promising frontier, opening new avenues for liver cancer research and treatment.

Survival Outcomes Associated With Radiological Progressive Disease Subtypes in Patients With Atezolizumab and Bevacizumab-Treated HCC.

To assess the relationship between survival outcomes and subtypes of radiological progressive disease (PD) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Atezo/Bev). A total of 462 patients with Atezo/Bev-treated HCC diagnosed with radiological PD during follow-up were enrolled. PD was classified into three categories: progression or emergence of intrahepatic lesions (PD-IH), macroscopic vascular invasion (PD-MVI), and extrahepatic spread lesions (PD-EHS). We defined PD-multiple as the presence of two or more PD categories. Subsequent analysis was categorized into the "PD-IH or PD-EHS" and "PD-MVI or PD-multiple" groups. The median progression-free survival (PFS) durations for patients with PD-IH, PD-MVI, PD-EHS, and PD-multiple were 5.3, 3.2, 3.9, and 3.5 months (p = 0.003). Patients with "PD-IH or PD-EHS" and "PD-MVI or PD-multiple" had median PFS of 5.2 and 3.5 months (p < 0.001). Median overall survival (OS) for PD-IH, PD-MVI, PD-EHS, and PD-multiple was 22.3, 15.1, 19.4, and 14.2 months (p = 0.002). The OS for patients with "PD-IH or PD-EHS" and "PD-MVI or PD-multiple" was 21.4 and 14.5 months (p < 0.001). Multivariate analysis demonstrated that ECOG-PS ≥ 1 (hazard ratio (HR), 1.508), α-fetoprotein levels ≥ 100 ng/mL (HR, 1.293), albumin-bilirubin grade ≥ 2 (HR, 1.573), liver cirrhosis (HR, 1.361), and PD subtypes PD-MVI or PD-multiple (HR, 1.735) were independently associated with OS. Patients with HCC undergoing Atezo/Bev treatment, diagnosed with PD-multiple (not solely based on IH or EHS) or PD-MVI, experienced poor prognosis, specifically in terms of OS.

Non-contrast magnetic resonance imaging versus ultrasonography for hepatocellular carcinoma surveillance: A randomized, single-center trial.

This study aimed to compare ultrasonography (US) and non-contrast magnetic resonance imaging (MRI) in the surveillance of hepatic malignancy. We conducted a randomized, non-blinded, single-center trial at a single center in South Korea. Eligible individuals were aged 20-70 years with liver cirrhosis, Child-Pugh class A, and no history of liver cancer or other recent malignancy. Participants were randomized 1:1 to receive up to ten semiannual surveillance using US or non-contrast MRI with serum alpha-fetoprotein testing. The primary endpoints were the detection rates of Barcelona Clinic Liver Cancer [BCLC] stage 0 or A tumors, stage distribution at initial diagnosis, and false-positive referral rates. From June 2015 to November 2017, 416 patients were screened, and 414 were enrolled and assigned to the US (n=207) or MRI (n=207) group. In total, 23 participants in US group and 25 in MRI group were diagnosed with liver cancer by November 2022. The detection rates of BCLC stage 0 or A tumors were not different between the US and MRI groups (8% [95% confidence interval (CI), 5 - 13%] versus 12% [8 - 17%]). BCLC stage 0 tumors were more prevalent in the MRI group than in the US group (8% versus 3%). The MRI group had earlier BCLC stage (P=0.014) and lower false-positive referral rate (0.7% [95% CI, 0.4 - 1.2%] versus 3.1% [2.3 - 4.1%], P <0.001) compared to the US group. Non-contrast MRI is a better alternative to US for the surveillance of cirrhotic patients offering earlier stage at initial diagnosis and lower false-positive referral rate. ClincalTrials.gov, NCT02514434.

Development and validation of a machine learning-based prediction model for hepatorenal syndrome in liver cirrhosis patients using MIMIC-IV and eICU databases

Hepatorenal syndrome (HRS) is a key contributor to poor prognosis in liver cirrhosis. This study aims to leverage the database to build a predictive model for early identification of high-risk patients. From two sizable public databases, we retrieved pertinent information about the cirrhosis patients’ therapies, comorbidities, laboratory results, and demographics. Patients from the eICU database served as a test set for external validation, while patients from the MIMIC database were divided into training and validation groups. Variables were screened using LASSO regression, Extreme Gradient Boosting (XG Boost), and Random Forest (RF). Core risk factors were determined from the intersection of the three methods. A predictive model was constructed using multivariable logistic regression and visualized via a nomogram. Model performance was assessed using ROC curves, decision curve analysis (DCA), clinical impact curves (CIC), and calibration curves. Eight critical variables associated with HRS were identified using machine learning methods. The final predictive model, based on five key variables—spontaneous bacterial peritonitis, red blood cell count, creatinine, activated partial thromboplastin time, and total bilirubin—showed excellent discrimination, with AUCs of 0.832 (95% CI 0.8069–0.8563) in the training set and 0.8415 (95% CI 0.8042–0.8789) in the validation set. The AUC in the external test set was 0.8212 (95% CI 0.7784–0.864). By integrating the MIMIC-IV database and machine learning algorithms, we developed an effective predictive model for HRS in liver cirrhosis patients, providing a robust tool for early clinical intervention.

P0427 Nutritional factors associated with the presence of non-alcoholic fatty liver disease (NAFLD) in patients with inflammatory bowel disease (IBD)

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent in patients with inflammatory bowel disease (IBD), not only due to the presence of chronic inflammation, but also due to the presence of dysbiosis and risk factors for metabolic disease. Due to the complications of NAFLD, evaluation of at-risk patients is recommended. Therefore, the objective of the study is to evaluate the nutritional status and body composition in IBD patients, comparing groups with and without NAFLD, and identifying the factors associated with NAFLD. Methods A cross-sectional study was conducted, assessing clinical data, metabolic syndrome presence, nutritional status, and biochemical markers. Patients were categorized into IBD+NAFLD and IBD-only groups based on hepatic ultrasound findings. Statistical analysis included descriptive statistics and logistic regression. Results In total, 129 IBD patients were included, 67 (51.94%) UC and 62 (48.06%) CD, 89 (68.99%) female, 31 (24.03%) with high blood pressure, 18 (13.95%) with dyslipidemia, and 16 (12.40%) with diabetes. Biological therapy was indicated in 65 (50.39%) patients. Clinical activity was observed in 60 (46.51%) of the patients. Presence of NAFLD was observed in 57 (44.19%) patients, being mild (43.86%), moderate (43.86%) or severe (12.28%). Factors associated with the presence of NAFLD were BMI (p&amp;lt;0.0001), overweight or obesity (p&amp;lt;0.0001), waist circumference (p&amp;lt;0.0001), arm circumference (p=0.0002), arm muscle area (p= 0.0136), waist-hip ratio (p=0.0215), calf circumference (p=0.0003), triceps skinfold (p=0.0086), fat mass (p=0.0001), visceral fat (p&amp;lt;0.0001), and hang- grip (p=0.0071). Regarding biochemical tests, patients with NAFLD presented alterations in creatinine (p=0.0343), AST (p=0.0018), ALT (p&amp;lt;0.0001), gammaGT (p&amp;lt;0.0001), ferritin (p=0.0107), glycemia (p=0.0017), glycated hemoglobin (p=0.0064), triglycerides (p&amp;lt;0.0001), basal insulin (p=0.0012). The presence of NAFLD was not associated with IBD activity (p=0.59) or with the use of medications (p&amp;gt;0,05). Conclusion The prevalence of NAFLD was high in the IBD population. Risk factors for NAFLD are related to metabolic syndrome. Patients should be investigated for the presence of NAFLD with the aim of controlling risk factors to avoid progression to complications such as liver cirrhosis.

The role and mechanisms of Helicobacter pylori outer membrane vesicles in the pathogenesis of extra-gastrointestinal diseases.

Helicobacter pylori (H. pylori) infection have been closely associated with several extra-gastrointestinal disorders. Outer membrane vesicles (OMVs), as lipid-membrane-bounded nanoparticles, are usually shed from Gram-negative both in vitro and in vivo. H. pylori is also capable of producing OMVs, which can enter the systemic circulation and be delivered to various cells, tissues or organs, eliciting a range of inflammatory and immune modulation responses. In this current review, we summarize the biogenesis and functions of H. pylori OMVs, describe the contribution of H. pylori OMVs to the generation and progression of extra-gastrointestinal diseases, such as neuronal damage, Alzheimer disease, hepatic fibrosis and atherosclerosis. We also explored the effect of H. pylori OMVs in inflammatory and immune modulation of diverse immune cells, including macrophages, mononuclear cells and dendritic cells. By elucidating the molecular mechanism of H. pylori OMVs-mediated extra-gastrointestinal diseases and immunomodulatory effect, it may promote the development of efficient treatments and vaccinations against H. pylori.

The Role of Solute Carrier Family Transporters in Hepatic Steatosis and Hepatic Fibrosis

The Role of Solute Carrier Family Transporters in Hepatic Steatosis and Hepatic Fibrosis

Impact of hypertension on liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease

BackgroundThis study aims to evaluate the association between hypertension and the risk of fibrosis in metabolic dysfunction–associated steatotic liver disease (MASLD) patients, as well as to investigate the impact of hypertension on the progression of liver fibrosis within this population.MethodsWe utilized data from the NHANES 2017 to March 2020. Multivariate logistic regression models were employed to control for sociodemographic and metabolic factors to determine the associations between hypertension, MASLD, and fibrosis.ResultsOf the total cohort (N = 5,967) 57.92% had hypertension, 38.8% had MASLD, 25.88% had both MASLD and hypertension. Patients with MASLD were more likely to have hypertension (64.24% vs. 44.80%). There was a significant association between stage I (OR1.70, 95% CI: 1.15–2.53) and stage II hypertension (OR1.98, 95% CI: 1.38–2.85) and an increased risk of SF. After adjusting for multiple confounding factors, stage I (OR1.59, 95% CI: 1.09–2.24) and stage II hypertension (OR1.48, 95% CI: 1.06–2.06) remained significantly associated with the risk of SF. Patients with both MASLD and hypertension had higher rates of SF at 14.83% and AF at 7.47%. After adjusting for sociodemographic factors, those patients still had an 8.02-fold increased risk of SF (OR8.02, 95% CI: 4.47–14.39) and a 15.13-fold increased risk of AF (OR15.13, 95% CI: 7.09–32.3). Further adjustment for metabolic factors, those patients still had a significantly higher risk of SF (OR3.07, 95% CI: 1.83–5.14) and AF (OR4.01, 95% CI: 1.48–10.89).ConclusionMASLD and hypertension are at risk for fibrosis, and the coexistence of the two has a more significant impact on the risk of fibrosis.

P0383 Factors associated with steatotic liver disease associated with metabolic dysfunction (MASLD) in patients with Inflammatory Bowel Disease (IBD)

Abstract Background IBD is characterized by a systemic inflammatory state. The dysbiosis found in these patients may lead to a possible increased risk of MASLD through intestinal bacterial translocation, and increased entry of lipopolysaccharides, free fatty acids and other toxins directly to the liver via the portal vein. The objective of this study is to evaluate the prevalence of MASLD in patients with IBD and the factors associated with this condition. Methods The presence of MASLD was based on the presence of hepatic steatosis associated with at least 1 metabolic criterion, and the exclusion of other liver disease in outpatients with IBD. Patients with BMI &amp;lt; 18.0 or BMI &amp;gt; 40 kg/m2, alcohol use or prednisone use &amp;gt; 20 mg/d were excluded. Results A total of 179 IBD patients were included: 95 with ulcerative colitis (UC) (53.1%) and 84 with Crohn’s disease (CD) (46.9%). The mean age was 45.1±14.4 years, 65.4% were female, and the mean disease duration was 10.9±7.8 years. Clinical activity was observed in 40. 45% and endoscopic activity in 49.70%. Biological therapy was used by 35.8% of UC patients and 71.4% of CD patients. In total, 72 (40.22%) patients had MASLD; 4 (2.23%) had MASH and 9 (5.02%) had liver fibrosis. Patients with MASLD were significantly older (48.3±12.6 vs. 43.0±15.2 years, p=0.0148) and had a higher prevalence of comorbidities, including diabetes (20.8% vs. 6.5%, p=0.0043), hypertension (30.6% vs. 12.2%, p=0.0023), dyslipidemia (25.0% vs. 7.5%, p=0.0011), and insulin resistance (61.4% vs. 19.4%, p&amp;lt;0.0001). MASLD patients also had higher BMI (29.1±3.6 vs. 24.5±4.0, p&amp;lt;0.0001), elevated blood glucose (100.1±23.8 vs. 87.3±17.9, p&amp;lt;0.0001), and triglycerides (186.9±107.5 vs. 117.6±59.9, p&amp;lt;0.0001), along with lower HDL-cholesterol (51.0±16.6 vs. 57.0±15.3, p=0.0098). Laboratory parameters including hematocrit (p=0.0035), hemoglobin (p=0.003), creatinine (p=0.017), CRP (p=0.0444), AST (p=0.0033), ALT (p&amp;lt;0.0001), gamma-GT (p&amp;lt;0.0001), and ferritin (p=0.0003) were also elevated in MASLD patients. There was no difference in disease characteristics such as extent of the inflammatory process, clinical (p=0.6131) or endoscopic activity (p=0.3877) or use of medications (p&amp;gt;0.05) between the groups. Conclusion We found a high prevalence of MASLD in patients with IBD, with a strong association to metabolic risk factors rather than disease activity. Therefore, early identification and management of metabolic syndrome and MASLD are critical to preventing liver disease progression and related complications in IBD patients.

Transcriptomic modifications across the genome and potential hazards of pulmonary fibrosis caused by metal-organic frameworks.

Metal-Organic Frameworks (MOFs) have shown great promise in environmental protection, owing to their exceptional properties including ultrahigh surface area and porosity, tunable pore size, and easy chemical functionalization. However, emerging evidence from experimental studies indicates that MOFs have side effects on human health due to metal ions doping, resulting in excessive reactive oxygen species (ROS) production, pro-inflammatory responses, and liver fibrosis. In this study, we investigated the impact of MOF-199 on human bronchial epithelial (HBE) cells by using transcriptome sequencing analysis. The results indicated that the stimulation of MOF-199 enhanced ROS generation, upregulated cytoplasmic Ca2+ levels, then activated the Grb2/SOS/Ras/Raf pathway, induced cell apoptosis, and ultimately resulted in lung fibroblasts through TGF-β secretion. The results were validated in vitro and in vivo. Therefore, it is necessary to carefully evaluate the nanosafety of MOF-199 in environment treatments.

Effects of silymarin on insulin resistance and sensitivity: A systematic review and meta-analysis of randomized controlled trials.

This study aims to evaluate the effect of silymarin on insulin resistance and insulin sensitivity through a systematic review and meta-analysis of randomized controlled trials (RCTs). We searched PubMed, Embase, Web of Science, and Cochrane Library up to September 2024 for relevant RCTs. The intervention required silymarin supplementation for at least 4weeks. Primary outcomes were homeostatic model assessment of insulin resistance (HOMA-IR) and fasting insulin (FI), while secondary outcomes included quantitative insulin sensitivity check index (QUICKI). Bias risk was assessed using Cochrane RoB 2. Subgroup analyses were based on disease type, duration, and dosage. Sensitivity and publication bias analyses were conducted using Egger's and Begg's tests. Statistical analysis and meta-analysis were performed using Stata 15.1. Six studies with 673 participants from Iran, Egypt, and Italy were included. All studies had low risk of bias. Meta-analysis showed that Silybum marianum significantly improved HOMA-IR (WMD = -2.29, 95% CI: -4.55 to -0.03, p=0.047) but had no effect on FI (WMD = -2.56, 95% CI: -7.60 to 2.48, p=0.862). Subgroup analyses revealed improvements in HOMA-IR for T2DM and diabetics with alcoholic cirrhosis, but no effect in non-alcoholic fatty liver disease (NAFLD) patients. QUICKI did not show significant changes in any group. Only one study reported changes in QUICKI. The results indicated that, compared to the placebo, silymarin improved insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). In conclusion, the results of this study indicate that there is limited evidence supporting the effectiveness of silymarin in improving HOMA-IR and FI levels in metabolic diseases, and it generally does not appear to significantly improve these parameters. Future studies should aim to increase the number of high-quality RCTs to further validate the efficacy and safety of silymarin, as well as to explore its underlying mechanisms.

Non-invasive methods for diagnosing portal hypertension and variceal bleeding due to liver cirrhosis secondary to NAFLD/MASLD: systematic review

BackgroundNon-alcoholic fatty liver disease (NAFLD), recently re-termed as metabolic dysfunction-associated steatotic liver disease (MASLD), is a global health concern affecting approximately 25% of adults. Complications such as portal hypertension and variceal bleeding are critical to diagnose but challenging with traditional invasive methods like hepatic venous pressure gradient (HVPG) measurement and esophagogastroduodenoscopy (EGD), which are not always feasible and carry risks.ObjectivesThis systematic review aim to evaluate the diagnostic accuracy of non-invasive methods for diagnosing portal hypertension and variceal bleeding in patients with NAFLD/MASLD cirrhosis, comparing these methods to invasive standards.MethodsA comprehensive literature search was conducted across PubMed, Cochrane Library, Google Scholar, and ScienceDirect from January 2000 to May 2024. Studies included evaluated non-invasive diagnostic techniques for portal hypertension and variceal bleeding, compared with HVPG and EGD, focusing on adult patients with confirmed NAFLD/MASLD cirrhosis. Data extraction covered study characteristics and diagnostic accuracy metrics. The quality of studies was assessed using the QUADAS-2 tool. Meta-analyses were performed using R and Python.ResultsEleven studies involving 2,707 patients met the inclusion criteria. Liver stiffness measurement (LSM) via transient elastography demonstrated high sensitivity (85%) and specificity (79%) for diagnosing clinically significant portal hypertension (CSPH) at a 20 kPa cutoff. For severe portal hypertension (SPH), LSM had a sensitivity of 81% and specificity of 85% at 25 kPa. Combining LSM with platelet count resulted in a sensitivity of 97% but lower specificity (41%) for CSPH. Spleen stiffness measurement (SSM) also showed good diagnostic performance with a sensitivity of 89% and specificity of 75% for CSPH.ConclusionNon-invasive tests, particularly LSM and SSM, show promise in diagnosing portal hypertension and variceal bleeding in NAFLD/MASLD cirrhosis. These methods offer high sensitivity, especially in combination, supporting their use in clinical settings to potentially reduce the need for invasive procedures. Future research should aim to standardize protocols and explore additional biomarkers to further enhance diagnostic accuracy.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?, identifier CRD42024567024.

P0579 Predictive Modeling for Colectomy Risk in Patients with Ulcerative Colitis and Primary Sclerosing Cholangitis: A Brazilian Multicentric Study Utilizing Machine Learning.

Abstract Background Ulcerative Colitis (UC) and Primary Sclerosing Cholangitis (PSC) are interrelated chronic inflammatory diseases. Patients with both conditions are at an elevated risk of colectomy, predominantly due to a higher incidence of dysplasia and colorectal cancer. Identify which patients are at higher risk of colectomy can be crucial to personalize their management. The primary objective was to develop a predictive model that can accurately forecast colectomy risk. Methods A cross-sectional study was conducted with patients from multiple tertiary centers across Brazil. We employed logistic regression and Random Forest (RF) models to analyze the data and identify significant predictors for colectomy. Data extraction was performed using Excel, and statistical analyses were conducted using R Studio. Results The study population comprised 83 individuals diagnosed with both UC and PSC. The mean age of the patients was 45 years (range 6 to 67), with 56 patients being male (67.5%). The mean age at diagnosis of UC and PSC was 32 years (range 18 to 77) and 36 years (range 8 to 72), respectively. Among patients with UC, the majority (74/83) had extensive colitis (89.2%), and 49.4% (41/83) had used at least one biological therapy. Only 13 patients (15.7%) required colectomy. Liver cirrhosis occurred in 15 cases (18.1%), and 11 patients (13.3%) required liver transplantation. Twelve patients (14.5%) had dysplasia or colorectal cancer. Our analysis identified several key predictors for colectomy. In the linear regression analysis, the duration of UC greater than 11 years significantly increased the risk of colectomy (OR=2.15, p=0.04). The presence of hepatic complications was associated with a tendency towards an increased risk of colectomy (OR=1.79, p=0.059). In the RF model, the presence of hepatic complications, and duration of UC greater than 11 years were significant predictors for colectomy. Protective factors identified by the RF model included use of biologic therapy, clinical and endoscopic remission. The RF model demonstrated an accuracy of 88.2%, outperforming the linear regression model and providing superior accuracy and robustness in predicting colectomy risk within the defined period. Conclusion Our study developed a predictive model using the RF algorithm, which demonstrated superior performance over linear regression in identifying high-risk patients for colectomy. This model can serve as a valuable tool in clinical practice, aiding in early intervention and tailored management strategies to mitigate severe outcomes in patients with UC and PSC. The use of RF provides a more reliable prediction, emphasizing the importance of machine learning in clinical decision-making. References Kim YS, Hurley EH, Park Y, Ko S. Treatment of primary sclerosing cholangitis combined with inflammatory bowel disease. Intest Res. 2023 Sep 1. doi:10.5217/ir.2023.00039. Epub ahead of print. PMID: 37519211. Kim YS, Hurley EH, Park Y, Ko S. Primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD): a condition exemplifying the crosstalk of the gut-liver axis. Exp Mol Med. 2023 Jul;55(7):1380-7. doi:10.1038/s12276-023-01042-9. PMID: 37464092; PMCID: PMC10394020. Greener JG, Kandathil SM, Moffat L, Jones DT. A guide to machine learning for biologists. Nat Rev Mol Cell Biol. 2022 Jan;23(1):40-55.

Modulation of PRL-1 within placental MSCs instigates the transition between EMT and MET subsequent to hepatic fibrosis.

Epithelial-to-mesenchymal transition (EMT) plays a crucial role in hepatic fibrogenesis and liver repair in chronic liver disease. Our research highlights the antifibrotic potential of placenta-derived mesenchymal stem cells (PD-MSCs) and the role of phosphatase of regenerating liver-1 (PRL-1) in promoting liver regeneration. We evaluated the efficacy of PD-MSCs overexpressing PRL-1 (PD-MSCsPRL-1) in a bile duct ligation (BDL)-induced rat injury model, focusing on their ability to regulate EMT. PD-MSCsPRL-1 significantly reduced mesenchymal markers by downregulating TGFB1/SMAD2, outperforming naïve PD-MSCs. The transplantation of PD-MSCsPRL-1 enhanced BMP7/SMAD1/5 expression, promoting epithelial marker expression and stimulating BMP7 within hepatocytes, modulating downstream SMAD signaling. Importantly, further validation confirmed that PRL-1 directly interacts with BMP7 in hepatocytes. PRL-1 expression in PD-MSCsPRL-1 restores TGFB1/BMP7 balance, promoting hepatic regeneration through mesenchymal-to-epithelial transition (MET). These findings highlight the therapeutic potential of engineered MSCs for liver disease and suggest innovative strategies for future stem cell therapies.

Resmetirom and thyroid hormone receptor‐targeted treatment for metabolic dysfunction‐associated steatotic liver disease (MASLD)

AbstractMetabolic dysfunction‐associated steatotic liver disease (MASLD) is a rapidly increasing chronic disease worldwide, particularly among patients with type 2 diabetes. Its severe form, metabolic dysfunction‐associated steatohepatitis (MASH), is also on the rise. The treatment of MASLD and MASH poses significant challenges. Thyroid hormones and their receptors thyroid hormone receptor (TR) agonists, especially resmetirom, have shown potential in improving metabolism and reducing liver inflammation. Thyroid hormones play a crucial role in regulating metabolism and maintaining physiological balance. However, in patients with MASLD, there is a reduced conversion of 3,3′,5,5′‐tetraiodo‐l‐thyronine (T4) to biologically active 3,5,3′‐triiodo‐l‐thyronine (T3), resulting in decreased T3 levels and impaired hepatic TR signaling. This hormonal imbalance is associated with disrupted hepatic lipid metabolism. Resmetirom, an oral selective TR agonist that specifically targets hepatocytes, was approved by the Food and Drug Administration (FDA) in March 2024 for the treatment of moderate to severe liver fibrosis in non‐cirrhotic adults with MASH. This approval was based on the results of the MAESTRO clinical program, which includes multiple‐stage research designs such as the MAESTRO‐NASH, MAESTRO‐NAFLD‐1, MAESTRO‐NAFLD‐OLE, and MAESTRO‐NASH‐OUTCOMES, aims to evaluate the efficacy and safety of resmetirom in different populations of MASH patient. Although the approval of resmetirom represents a significant milestone in the treatment of MAFLD and MASH, many questions remain regarding its long‐term effectiveness and impact on clinical outcomes. Ongoing research, particularly through the MAESTRO program, holds promise for providing additional insights into the long‐term management of MASLD using resmetirom and other similar medications.

P1310 Role of gut pathobiont-derived membrane vesicles for biliary epithelium in PSC-IBD

Abstract Background Primary sclerosing cholangitis (PSC), a cholestatic liver disease highly associated with inflammatory bowel disease (IBD), is characterized by progressive inflammatory destruction of bile ducts. Bacterial membrane vesicles (bEVs) derived from gut pathobionts may play a significant role in the pathogenesis of PSC-IBD by disrupting the biliary barrier, promoting liver inflammation and contributing to liver fibrosis. A deeper understanding of how bEVs influence bile duct homeostasis is crucial for unraveling the mechanisms behind PSC-IBD and developing targeted therapeutic strategies. Methods Bile duct organoids were generated from WT mice and PSC-IBD patients. BEVs were isolated from commensals or PSC-associated gut pathobionts following MISEV guidelines. To assess the role of bEVs to ductal barrier dysfunction and inflammation, we employed an organoid based permeability assay, immunofluorescence staining, qPCR and bulk RNA sequencing. Furthermore, to investigate whether the presence and amount of bEVs in the systemic circulation were associated with PSC-IBD, we analyzed serum-derived EVs from either healthy control, as well as PSC and PSC-IBD patients using Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and a TLR4-Receptor based reporter assay. Results Our results demonstrate that particularly bEVs isolated from gut pathobionts trigger signaling pathways associated with inflammation in both murine and human biliary epithelial cells. Furthermore, we observed a disease and strain specific fingerprint after bEV treatment, which was characterized by several significantly enriched terms related to PSC-related inflammation, including genes involved in T-helper 17 cell differentiation, and tumor necrosis factor (TNF) signaling. However, we did not observe a direct impact of bEVs on biliary barrier function. Consistent with this, we detected increased levels of bEVs in the systemic circulation of PSC-IBD patients, but not in those with PSC alone or in healthy controls, suggesting that these bacterial components may translocate across a compromised intestinal barrier into the bloodstream. Conclusion Overall, our study suggests that bEVs may contribute to biliary inflammation, but not barrier dysfunction and thereby may represent a novel player in the pathogenesis of PSC-IBD. Additionally, it underscores the critical role of bEVs in host-microbe communication, suggesting their potential as diagnostic biomarkers and highlighting, that therapeutic strategies targeting bEVs could offer promising avenues for managing PSC-IBD.

PBMCs gene expression predicts liver fibrosis regression after successful HCV therapy in HIV/HCV-coinfected patients

BackgroundHCV eradication with antiviral treatment reduces hepatic disease, but some patients remain at risk of progression to cirrhosis despite HCV clearance. We aimed to examine the association between peripheral blood mononuclear cells (PBMCs) gene expression before HCV therapy and a pronounced decrease in the liver stiffness measurement (LSM) value in HIV/HCV-coinfected patients after HCV treatment and achievement of sustained virological response (SVR).MethodsWe performed a retrospective study in 48 HIV/HCV-coinfected patients who started anti-HCV treatment with at least advanced fibrosis (LSM ≥9.5). Total RNA was extracted from PBMCs at baseline, and poly(A) RNA sequencing was performed. The outcome was an LSM reduction greater than 50% (LSMred&amp;gt;50%) about 48 weeks after HCV treatment.ResultsSeven patients (14.5%) reduced LSM by over 50%. We found 47 significant differentially expressed (SDE) genes associated with reaching an LSMred&amp;gt;50% after achieving HCV eradication, 42 upregulated and 5 downregulated in the LSMred&amp;gt;50% group. Ten and five of these upregulated genes were classified into two significantly enriched KEGG pathways: cell cycle and progesterone-mediated oocyte maturation (q-value &amp;lt;0.05), respectively. Two SDE genes achieved excellent discrimination ability: NCAPG had an AUROC of 0.908, NHLRC1 of 0.879, and a logistic regression model with these two genes of 0.955.ConclusionA pre-treatment gene expression signature in PBMCs was associated with liver fibrosis regression (LSMred&amp;gt;50%) after achieving HCV clearing with HCV therapy in HIV/HCV-coinfected patients, where two SDE genes (NCAPG and NHLRC1) showed the greatest predictive capacity, which could be used as a noninvasive marker of liver fibrosis regression.