Hepatic Encephalopathy Research Articles

Paediatric acute liver failure: early outcome and evaluation of transplantation criteria in a Belgian transplantation centre

BackgroundOne of the challenges when caring for children admitted for acute liver failure (ALF) is to quickly identify those who will improve spontaneously and those for whom liver transplantation (LT) is the only therapeutic option.MethodsRetrospective study to review our experience, identify mortality risk factors and update our LT criteria in case of paediatric ALF.Results111 children were admitted between March 1989 and May 2021 (mean age 59.1 months). 28 children never met our LT criteria; 17 had contraindication to LT; 66 were registered on the LT waitlist. 14 of these 66 were subsequently withdrawn because of spontaneous liver function recovery; 11 died before having received a liver; 41 were transplanted. Hospital survival rate was 63% for the whole series, 98% for the children without LT criteria and 71% for the transplanted children. Univariate analysis identified cardiovascular and respiratory failures on admission, and grade 4–5 hepatic encephalopathy (HE) during stay significantly associated with death. Non-survivors also had, on admission and during their stay, significantly higher levels of lactate, ammonia and bilirubin and, during their stay, significantly more frequent prothrombin time ≤ 25% or international normalized ratio ≥ 4.0 than the survivors. Multivariate analysis identified grade 4–5 HE, lactate level on admission and ammonia peak level as significant mortality risk factors.ConclusionOur criteria identified almost all children who had the capacity to spontaneously recover their liver function and suggest that updated criteria should combine biological tests and signs of multiple organ failure.

Protective Effects of Lemna minor Linn. On Hepatic and Cognitive Impairments in Acetaminophen Induced Hepatic Encephalopathy in Rats

Aim: Lemna minor Linn., an aquatic plant, is a promising novel therapeutic agent that has been traditionally used in ethnobotanical practices as an ecofriendly supplement for the management of various ailments. This study involves the evaluation of ethanolic extract of Lemna minor Linn. against Paracetamol-induced Hepatic Encephalopathy using in vitro and in vivo Models. Methods: The acute oral toxicity study of the ethanolic extract of Lemna minor (EELM) was conducted following the OECD-425 guidelines over a 14-day period. A total of nine animals were used for this toxicity assessment. The EELM was tested in Paracetamol(PCM)-induced bioactivation animal model at two different dosages 200 and in comparison with silymarin as a standard compound. The In vivo experimental study was conducted using Sprague Dawley rats which was divided into 5 groups each group containing 6 animals so the total no of animals used in the study was 30 animals. The treatment groups included: normal control ( ), 100mg/kg silymarin (standard) and the EELM of two different doses of 200 and , p.o were administered to rats 10 hr before paracetamol ( ) treatment. Rats were orally administered their respective doses every day for total 30days. Paracetamol-induced oxidative liver damage disrupted normal levels of liver enzymes, total protein, and bilirubin, while also depleting antioxidant reserves. This oxidative stress was strongly associated with paracetamol toxicity, leading to a marked depletion of glutathione (GSH) and impairing both memory and cognitive function in the animals. Behavioral parameters are performed to evaluate the effect of drugs on cognitive behaviour of animals. Morris water maze test was performed to study how animals learn and remembers the spatial information relying on distal cues to locate the hidden platform in an opaque water. Additionally, elevated plus maze was performed to measures the anxious behaviour of rats, the criterion was tested based on the conflict between rats innate instincts to explore new environment and avoid open, well-lit areas. The potential protective effects of EELM was evaluated by measuring serum enzyme levels and antioxidants status in the liver and brain, further histopathological analysis was performed respectively. Results: The acute toxicity study did not report any mortality or toxicity signs in animals. PCM toxicity led to a statistically increase in the liver and body weight, along with brain water content. The PCM-intoxicated group exhibited a marked reduction in the level of superoxide dismutase (SOD) and glutathione (GSH) in the brain and liver, as well as an increase in lipid peroxidation and serum biomarkers (AST, ALT, ALP, and total bilirubin). EELM significantly ( ) reduced liver injury by inhibiting ALT, AST and ALP levels in serum. SOD, GSH and MDA liver content were significantly ( ) elevated by EELM, compared to PCM treated rats. Comparing the treatment and induced group, the treated group successfully recovered the activity of antioxidant levels and also been acknowledged for restored liver functioning by alleviating oxidative stress and also GSH level in brain was significantly increased by EELM and preserved the histology of brain, which was chronically produced over a period of 30 days. Conclusion: The findings of this investigation indicate the traditional use of Lemna minor in hepatoprotection and neuroprotection by regulating oxidative stress and mitigating reactive oxygen species (ROS). The insights gained from this research contribute to the development of novel therapeutic agents and paves the way for further studies on Lemna minor to enhance health outcomes, particularly in the management of neurodegenerative diseases.

Longitudinal Evolution of the Brain Microstructure in Cirrhotic Patients on Diffusion Kurtosis Imaging.

Although improvement of cognitive function after liver transplantation has been demonstrated in several neuropsychological studies, there is limited research on longitudinal changes in the cirrhotic patients' brain structure before and after transplantation. To investigate longitudinal changes of brain microstructure in cirrhotic patients using diffusion kurtosis imaging (DKI). Prospective. A total of 153 cirrhosis patients, comprising 60 hepatic encephalopathy (HE) patients (16 females/44 males) and 93 no-HE patients (35 females/58 males), along with 93 healthy controls (HCs) (53 females/40 males) were enrolled. Subsequently, 58 recipients completed 1-month postoperative follow-up, 29 patients completed 1-, 3-months, and 17 patients completed 1-, 3-, 6-month follow-up. Spin-echo single-shot echo-planar sequence using a 3.0 T scanner. Diffusion kurtosis estimator software was used to estimate the DKI parameter maps by a MR imaging physicist (Y.-Y.C. with 12 years of experience). The diffusion metrics (eg, radial kurtosis [RK], mean kurtosis, fractional anisotropy, mean diffusivity) of the patients before transplantation were compared with those of the HCs using voxel-wise analysis of variance (ANOVA), along with t tests for post hoc analysis. Linear mixed-effects models were applied to the longitudinal data. We imposed a cluster level Family Wise Error (FWE) correction rate of PFWE = 0.05 with voxel-wise cutoff of P = 0.001 together with a cluster-size cutoff of N ≥ 56, and generated smoothness estimates from the preprocessed data using the mixed-model autocorrelation function. The RK metrics of the patients decreased significantly in the anterior cingulate cortex (HE/no-HE < HC, ANOVA-F = 21.91). After transplantation, the RK of the pallidum showed a continuous upward trend (time effect T = 11.26); whereas the RK of the right postcentral gyrus showed a continuous downward trend (time effect T = -9.56). In addition, the RK in superior longitudinal fasciculus showed new-onset decrease after transplantation. Longitudinal changes in DKI metrics reveal the course of brain microstructural changes before and after transplantation in cirrhotic patients, potentially associated with cognitive alterations after surgery. 1 TECHNICAL EFFICACY: Stage 4.

Evaluation of Patients with Hepatic Cirrhosis due to Etiology for the Complication

Objectives: Hepatic cirrhosis is a disease with high mortality. The leading causes of morbidity and mortality in patients with hepatic cirrhosis are disease-associated complications. We aimed to describe the association between the difference in laboratory parameters, complications, and commonly known causes of cirrhosis, such as hepatitis B, hepatitis C, alcoholic liver disease (NASH), and autoimmune hepatitis. Methods: We investigated 541 patients with different etiologies of cirrhosis who applied to a gastroenterology clinic from 2009 to 2018 in Florance Nightingale Hospital. All patients were divided into five groups according to the etiology of cirrhosis, such as hepatitis B, hepatitis C, alcoholic liver disease (ALD), NASH, and autoimmune hepatitis. Biochemical and metabolic parameters were evaluated between five groups. Results: 83 patients with alcoholic liver disease, 242 patients with hepatitis B-associated cirrhosis, 112 patients with hepatitis C-associated cirrhosis, 77 patients with NASH, and 27 patients with autoimmune hepatitis were enrolled. Laboratory parameters due to the etiology of hepatic cirrhosis are shown in Table 2. Ascites and hepatic encephalopathy were statistically higher in alcoholic liver disease, hepatitis B, and NASH cirrhosis, while esophageal variceal bleeding was higher in NASH and autoimmune hepatitis. Spontaneous bacterial peritonitis was statistically higher only in cirrhosis due to autoimmune hepatitis. Conclusion: It is very important to assign complications that may develop in liver cirrhosis and manage them by etiology.

Sleep disturbance in patients with cirrhosis and transjugular intrahepatic portosystemic shunt

BackgroundSleep disturbance (SD) is a common occurrence in individuals with cirrhosis and significantly impacts their quality of life. Datas regarding post transjugular intrahepatic portosystemic shunt (TIPS) SD are scarce. This study aimed to explore the incidence and outcomes of post-TIPS SD.MethodsFrom August 2018 to November 2019, 73 patients who underwent TIPS were prospectively recruited for the study. Sleep quality was evaluated via the Pittsburgh Sleep Quality Index (PSQI), and the presence of hepatic encephalopathy was evaluated according to the West Haven criteria before and after the TIPS procedure.ResultsNineteen patients (26%) experienced new-onset SD after TIPS, with a median latency of 67 (40–98) days from the procedure. The median time from TIPS creation to occurrence was 67 (40–98) days. Minimal hepatic encephalopathy (MHE) post-TIPS emerged as an independent predictor of SD, with an odds ratio of 3 (95% CI: 1.04–8.78, P = 0.046). Notably, five of the six (83%) patients with SD experienced improvement after being administered eszopiclone. Ten of the thirteen (77%) patients with SD improved spontaneously without treatment. Furthermore, the prevalence of MHE was significantly greater among patients with SD than among those without SD (58% vs. 31%, P = 0.04).ConclusionsSD is prevalent in patients who undergo TIPS. MHE is an independent risk factor for the development of SD post-TIPS. Eszopiclone may be a safe and effective treatment option for patients with SD after TIPS. The study was registered with ClinicalTrials.gov under the identifier NCT03685994, with a registration date of September 23, 2018.

Impact of Karnofsky performance status on outcomes of patients with severe alcohol-associated hepatitis: a propensity-matched analysis.

Severity scores, including the model for end-stage liver disease (MELD) and discriminant function score, guide the treatment of patients with severe alcohol-associated hepatitis (AH). We aimed to investigate the impact of functional status on outcomes of patients with AH. Medically managed patients (n = 133) with AH from 1 January 2019 to 31 December 2022 were included in this prospective study. The objectives were to compare the long-term survival, recompensation rates, corticosteroid response, incidence of infections, hepatic encephalopathy (HE) and acute kidney injury (AKI) among propensity score-matched patients with good Karnofsky performance status (KPS) (score ≥50) and poor KPS (score <50) using Kaplan-Meier analysis. Twenty-five patients with good KPS were matched with 25 patients with poor KPS and followed up for a median duration of 10 (0.5-33) months. Survival was 76% (19/25; 95% confidence interval (CI), 54.9-90.6) in patients with good KPS compared to 42.3% (11/25; 95% CI, 23.4-63.1) patients with poor KPS (P = 0.001) at 10 months. The recompensation rate was higher in the good KPS group than in the poor KPS group (68% vs 44%; P = 0.04). A higher proportion of patients in the good KPS group (78.9%) than in the poor KPS group (42.8%; P = 0.03) responded to corticosteroids. Survival was lower among non-responders in the poor KPS group (0% vs 75%; P = 0.01). The proportion of patients who developed infection (36% vs 28%; P = 0.051), HE (36% vs 12%; P = 0.01) and AKI (60% vs 16%; P < 0.001) was higher in patients with poor KPS than in good KPS. KPS is an important determinant of outcomes in patients with AH, including survival, recompensation, response to corticosteroids and complications.

Clinical Presentation And Etiology of Acute Hepatitis In Children: An Experience From A Tertiary Centre of Bangladesh

Background: The prevalence of Acute hepatitis is still high in developing countries even though the availability of vaccines, prophylactic measures and improved sanitation. Objective: To investigate clinical features, biochemical parameters and etiology of acute hepatitis among hospitalized children in a tertiary care center. Method: This cross sectional study was conducted in the Department of Pediatrics Dhaka Medical College Hospital between June 2021 to July 2022.A total of 120 children aged bellow 15 years who presented with acute hepatitis were included in the study. Results: Most of the studied children were in 5-10 years age group 73(61%).Most of the children presented with jaundice 112 (93.3%), nausea &amp; vomiting 105(87.5%),low grade fever 73(61%),upper abdominal pain 79(65.8%), pruritus 15(12.5%), melena 12(10%), pale stool 10(8.3%), anicteric 8(6.6%). On physical examination tender hepatomegaly was found 110(91.6%) cases, just palpable spleen 8(6.6%), hepatic encephalopathy 6(5%), ascites 4(3.3%) cases. Among the studied patients 102 (85%) were having herbal or homeopathic medicines at the time of admission. All of patients had increase serum bilirubin and ALT and most of them 79(65.8%) had ALT between 500-1500 IU/L.AST was also raised. Increase prothrombin time/INR 17(14.1%) and low serum albumin was seen in7 (5.8%) cases. Majority cases were HAV 81 (67.5%), followed by HEV 10 (8.3%), non A and non B 9(7.5%), HBsAg &amp; anti-HBcIgM were found with positive 4 (3.3%) cases, HAV with HEV co-infection 3 (2.5%). Other than viral hepatitis Salmonella positive 5(4.1%), drug induced hepatitis due to anti-TB and valproic acid 3(2.5%) cases,3(2.5%) cases Wilson’s disease and 2(1.7%) following Wasp bite. Conclusions: The study found the common presenting features of acute hepatitis were jaundice, anorexia, nausea, vomiting, fever, abdominal pain, tender hepatomegaly and ascites. Acute hepatitis due to HAV was the commonest followed by HEV. Vaccination programme should be taken by government to control hepatitis A in children. J Dhaka Med Coll. 2023; 32(1) : 32-37

Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin.

Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health1. Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode of action2, but for which resistance has been widely reported but is unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in patients with liver disease3, causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterized operon (prdRAB) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered 'low risk' for the development of antibiotic resistance. Our study shows that this assumption is flawed and that widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics.

Hepatic Encephalopathy Without Hyperammonemia in the Setting of Liver Metastases by a Pancreatic Neuroendocrine Tumor

Hepatic Encephalopathy Without Hyperammonemia in the Setting of Liver Metastases by a Pancreatic Neuroendocrine Tumor

Nomograms for predicting short-term mortality in acute-on-chronic liver disease caused by the combination of hepatitis B virus and alcohol.

This study aimed to identify predictive factors for the prognosis of acute-on-chronic liver disease (AoCLD) due to both hepatitis B virus (HBV) and alcohol and to develop prognostic models to improve treatment management. AoCLD patients with HBV and alcohol as etiological factors were selected from two multicenter prospective cohorts (NCT02457637,NCT03641872) and included in separate training and validation cohorts (n = 180 and n = 148). In the training cohort, the CATCH-LIFE A nomogram (based on age, bilirubin, international normalized ratio, serum sodium, and hepatic encephalopathy score) and CATCH-LIFE B nomogram (based on age, bilirubin, international normalized ratio, serum albumin, white blood cell, platelet count, and hepatic encephalopathy score) had discriminatory ability for predicting 28-day (c-indexes of 0.910 and 0.899) and 90-day mortality (c-indexes of 0.878 and 0.887, respectively). The area under the curve values for 28-day and 90-day mortality prediction by the CATCH-LIFE A nomogram were 0.922 (95% CI : 0.874, 0.971) and 0.905 (0.856, 0.956), respectively, while those for the CATCH-LIFE B nomogram were 0.916(0.861,0.972) and 0.915 (0.866,0.964), respectively. Similar performance results were observed in the validation cohort. Optimal cut-off scores for each nomogram could be used for patient stratification in high- and low-risk groups, and the high-risk groups showed shorter survival times than the low-risk groups in both the training and validation cohorts. Two nomograms constructed from the first short-term follow-up data from patients with AoCLD due to combined HBV infection and alcohol exposure showed good predictive performance for 28-day and 90-day mortality and might be used to guide clinical management.

Comparison of outcomes for transjugular intrahepatic portosystemic shunt creation: Viatorr versus Fluency versus a bare stent/Fluency stent combination

PurposeTo compare clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) created with the single covered-uncovered stent (Viatorr TIPS Endoprosthesis) versus covered stent (Fluency) versus a combination of covered and uncovered stent.Materials and methodsFrom May 2016 and July 2019, a total of 180 liver cirrhosis patients with recurrent variceal bleeding underwent TIPS creation with single covered-uncovered stent (n = 63) or covered stent (n = 41) or a covered and uncovered stent combination (n = 76). Shunt dysfunction, rebleeding, overt hepatic encephalopathy and mortality was estimated using the Kaplan–Meier method and compared with the log-rank test.ResultsThe difference of baseline characteristics among these three groups were not significant. The included patients had a median age of 51 years (IQR 43–61), and 101 (56.1%) were men. The 1-year and 2-year shunt dysfunction rates were 1.6% and 3.2% in the single covered-uncovered stent group, 7.3% and 7.3% in the covered stent group and 5.3% and 6.6% in the combination group, respectively. There was no significant difference among groups [Hazard Ratio (HR) (95%CI): 1 vs 2.29 (0.38 − 13.72) vs 2.10 (0.41 − 10.83); P = 0.913]. No significant differences in the incidence of all-cause rebleeding were observed between the groups at 1 year (Viatorr vs Fluency vs combination: 11.1% vs 17.1% vs 10.5%) as well as 2 years (15.9% vs 17.1% vs 11.8%), with the HR (95%CI) being 1 vs 1.27 (0.5—3.21) vs 0.74 (0.30–1.82); P = 0.475). The 1-year and 2-year incidence of overt hepatic encephalopathy were 30.2% and 30.2% in the single covered-uncovered stent group, 22.0% and 22.0% in the covered stent group and 25.0% and 25.0% in the combination group, respectively. However, there was no significant difference among these three groups (P = 0.402). In addition, there was no significant difference in the 1-year and 2-year mortality (6.3% and 7.9% vs. 4.9% and 9.8% vs. 6.6% and 9.2%, P = 0.606).ConclusionNo significant difference was observed among different stent groups. Fluency covered stent and the generic bare stent/Fluency covered stent was not an unreasonable alternative to the Viatorr stent for TIPS creation.

Serum Autotaxin Levels Predict Liver-Related Events in Primary Biliary Cholangitis Patients: A Long-term Multicenter Observational Study

Background: A straightforward, reliable, and noninvasive method for predicting the development of liver-related events (LRE) in primary biliary cholangitis (PBC) has not been attained thus far. The present study investigated whether serum autotaxin (ATX) could predict liver-related events (LRE) in PBC patients. Methods: This retrospective multicenter investigation included 190 biopsy-proven untreated PBC patients. All subjects were followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, esophagogastric varices, ascites, and hepatic encephalopathy, was investigated in relation to ATX levels at the time of liver biopsy Results: During the median follow-up period of 9.7 years, LRE were observed in 22 patients (11.6%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE were 0.80 and 1.086 mg/L, respectively. Patients with serum ATX ≥ 1.086 had a significantly higher cumulative incidence of LRE compared with patients with ATX &lt; 1.086 (33.3% vs. 3.6%, p &lt; 0.00001). Notably, the predictive capability of ATX for LRE in PBC patients surpassed that of FIB-4, ALBI, APRI, and M2BPGi. A multivariate Cox proportional hazards model revealed ATX as an independent associated factor for LRE (hazard ratio 6.24, 95% confidence interval 1.87-20.80, p = 0.003) along with Nakanuma stage (hazard ratio 2.75, 95% confidence interval 1.52-4.99, p &lt; 0.001). These results were closely replicated in a serologically diagnosed PBC validation cohort (n = 32). Conclusion: Serum ATX levels may serve as a predictive marker for LRE in patients with PBC.

Serum zinc levels as predictors of covert hepatic encephalopathy in patients with liver cirrhosis.

Covert hepatic encephalopathy (CHE) significantly impacts the quality of life and prognosis in patients with liver cirrhosis. This study aims to analyze the prevalence and risk factors of CHE to identify high-risk patients who would benefit from therapeutic interventions. This single-center, retrospective observational study included 126 patients without a history of overt hepatic encephalopathy (OHE). CHE was defined as a score above the age-based cutoff value in the Stroop test. Factors associated with the occurrence of CHE and the subsequent development of OHE were evaluated. CHE was detected in 47 patients (37.3%). A multiple logistic regression analysis identified serum zinc levels (per + 1µg/dL, odds ratio 0.95, P = 0.0007) as the only risk factor associated with CHE, with a cutoff value of 60µg/dL (AUC 0.71, P = 0.0001). Neither blood ammonia levels nor liver function were predictive of CHE. During a median observation period of 211days, OHE developed in 18 patients (14.3%). The administration of more than 20mg of furosemide was identified as a risk factor for developing OHE (hazard ratio 23.52, P = 0.0207). Cirrhotic patients with serum zinc levels below 60µg/dL exhibit a high risk of developing CHE, regardless of blood ammonia levels. These patients face a significant risk of developing OHE. Therefore, early zinc supplementation is recommended for the prevention of OHE, particularly for those prescribed 20mg or more of furosemide.

Mesenteric Vein to Gonadal Vein Shunt Embolization in Patients with Portal Hypertension: Technical Considerations and Clinical Outcomes.

To assess the technical and clinical outcomes of percutaneous embolization for high-flow mesenteric vein to gonadal vein (MGV) portosystemic shunts. In this HIPPA-compliant, review board-approved study, patients who underwent embolization of MGV shunts between 2011 and 2023 were included. Patient demographic data, embolization technique, clinical outcomes, and complications were retrieved from the electronic health records. Technical success was defined as complete occlusion of the shunt on follow-up imaging. Clinical outcomes assessed were resolution/improvement of hepatic encephalopathy, improvement in liver function, changes to liver volumes, and occurrence of adverse events. Eight patients (mean age 59.5, 75% female) with nine MGV shunts were included. The indications for shunt embolization included medically refractory hepatic encephalopathy, bleeding duodenal varices, and transplant liver dysfunction. The mean maximum shunt diameter was 23.3mm. Embolization was most commonly performed with a combination of coils and N-butyl cyanoacrylate or vascular plugs. Complete MGV shunt thrombosis was achieved in 7/9 shunts post-embolization, and symptom improvement was noted in 7/8 patients. Child-Pugh scores improved post-embolization in 6/9 patients by a median of 3 points. Liver volumes also increased by a mean of 20.8 ± 17.7% post-embolization. Minor adverse events included new onset ascites, partial mesenteric/portal vein thrombosis, and new gastroesophageal varices without bleeding in four patients. Embolization of MGV shunts is technically feasible and effective for treatment of hepatic encephalopathy and increasing hepatopetal portal perfusion. There was an improvement in Child-Pugh scores and an increase in liver volumes in the majority of patients post-embolization.

Preemptive Transjugular Intrahepatic Portosystemic Shunt in Variceal Bleeding: A Real-World Study in a Tertiary Hospital

Introduction: Several studies have highlighted the potential benefits of early prophylactic transjugular intrahepatic portosystemic shunt (preemptive TIPS) placement in reducing morbidity and mortality following variceal bleeding (VB). Baveno VII recommends its placement less than 72 h after VB (Child-Pugh class C <14 or class B >7 plus active bleeding). This study aimed to evaluate the effectiveness of preemptive TIPS compared to a control group in a referral center. Methods: The control group included cirrhotic patients with VB and Child-Pugh class C or B with active bleeding, retrospectively selected between 2016 and 2022 and divided into 2 subgroups: those that never underwent TIPS placement during the course of their illness (subgroup A) and those submitted to TIPS placement due to rebleeding (subgroup B). Additionally, patients who received preemptive TIPS placement between August 2022 and January 2024 were prospectively included into the preemptive transjugular intrahepatic portosystemic shunt (pTIPS) group. Results: A total of 47 patients were included, 19 (40.4%) in the pTIPS group and 28 (59.6%) in control group (17 in subgroup A). There were no differences in baseline characteristics between the groups, except hepatic encephalopathy that was significantly higher in the control group when compared to the pTIPS group: 19 (67.9%) versus 6 (31.6%), p = 0.014. Early rebleeding rates were significantly lower in the pTIPS group: 1 (5.3%) versus 13 (46.4%) (p = 0.002). There were no significant differences in 6-week survival between the groups: 25 (89.3%) versus 17 (89.5%), p = 0.683. Regarding hepatic encephalopathy, no significant differences were observed between the control and the pTIPS group: 6 (21.4%) versus 4 (21.1%), p = 0.632, even when comparing subgroup A (4, 23.5%) with the pTIPS group (p = 0.432). Conclusion: This real-world study highlights the potential benefits of preemptive TIPS placement in reducing early relapse of VB, thereby lowering morbidity and complications. The findings advocate for the proactive incorporation of preemptive TIPS into clinical practice to optimize patient outcomes following VB.

Extracellular Vesicles from Mesenchymal Stem Cells Reverse Neuroinflammation and Restore Motor Coordination in Hyperammonemic Rats.

Cirrhotic patients may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor deficits. Hyperammonemia and inflammation are the main contributors to the cognitive and motor alterations of MHE. Hyperammonemic rats reproduce these alterations. There are no specific treatments for the neurological alterations of MHE. Extracellular vesicles from mesenchymal stem cells (MSC-EVs) are promising to treat inflammatory and immune diseases. We aimed to assess whether treatment of hyperammonemic rats with MSC-EVs reduced neuroinflammation in cerebellum and restored motor coordination and to study the mechanisms involved. The effects of MSC-EVs were studied in vivo by intravenous injection to hyperammonemic rats and ex vivo in cerebellar slices. Motor coordination was analyzed using the beam walking test. Effects on neuroinflammation were assessed by immunohistochemistry, immunofluorescence and Western blot. Injection of MSC-EVs reduced microglia and astrocytes activation in cerebellum and restored motor coordination in hyperammonemic rats. Ex vivo experiments show that MSC-EVs normalize pro-inflammatory factors, including TNFα, NF-kB activation and the activation of two key pathways leading to motor incoordination (TNFR1-NF-kB-glutaminase-GAT3 and TNFR1-CCL2-BDNF-TrkB-KCC2). TGFβ in the EVs was necessary for these beneficial effects. MSC-EVs treatment reverse neuroinflammation in the cerebellum of hyperammonemic rats and the underlying mechanisms leading to motor incoordination. Therapy with MSC-EVs may be useful to improve motor function in patients with MHE.

Evaluating the positive predictive value of code-based identification of cirrhosis and its complications utilizing GPT-4.

Diagnosis code classification is a common method for cohort identification in cirrhosis research, but it is often inaccurate and augmented by labor-intensive chart review. Natural language processing (NLP) using large language models (LLMs) is a potentially more accurate method. To assess LLMs' potential for cirrhosis cohort identification, we compared code-based versus LLM-based classification with chart review as a "gold standard." We extracted and conducted a limited chart review of 3,788 discharge summaries of cirrhosis admissions. We engineered zero-shot prompts using Generative Pre-trained Transformer (GPT)-4 to determine whether cirrhosis and its complications were active hospitalization problems. We calculated positive predictive values (PPVs) of LLM-based classification versus limited chart review, and PPVs of code-based versus LLM-based classification as a "silver standard" in all 3,788 summaries. Versus gold standard chart review, code-based classification achieved PPVs of 82.2% for identifying cirrhosis, 41.7% hepatic encephalopathy, 72.8% ascites, 59.8% gastrointestinal bleeding, and 48.8% spontaneous bacterial peritonitis. Compared to chart review, GPT-4 achieved 87.8-98.8% accuracies for identifying cirrhosis and its complications. Using LLM as a silver standard, code-based classification achieved PPVs of 79.8% for identifying cirrhosis, 53.9% hepatic encephalopathy, 55.3% ascites, 67.6% gastrointestinal bleeding, and 65.5% spontaneous bacterial peritonitis. LLM-based classification was highly accurate versus manual chart review in identifying cirrhosis and its complications - this allowed us to assess the performance of code-based classification at scale using LLMs as a silver standard. These results suggest LLMs could augment or replace code-based cohort classification and raise questions regarding the necessity of chart review.

Mechanism of Alzheimer type II astrocyte development in hepatic encephalopathy

Type C hepatic encephalopathy (Type C HE) is a major and complex neurological condition that occurs following chronic liver failure. The molecular basis of Type C HE remains elusive. Type C HE is characterized by mental confusion, cognitive and motor disturbances. The presence of Alzheimer type II astrocytes (AT2A) is the key histopathological finding observed in Type C HE. However, nothing is currently known regarding AT2A development and its involvement in cognitive, and motor deficits in Type C HE. We, therefore, examined in rats the mechanisms by which liver failure contributes to the progression of AT2A, and its role in the development of cognitive and motor deficits in thioacetamide (TAA) model of Type C HE. We and others earlier reported increased oxidative/nitrosative stress (ONS), JNK1/2, and cMyc activation in ammonia-treated astrocyte cultures, as well as in brains from chronic liver failure. We now found increased levels of astrocytic glia maturation factor (GMF, a factor strongly implicated in neuroinflammation), as well as various inflammatory factors (IL-1β, TNF-α, IL-6, MMP-3, COX2, CXCL1, and PGE2), and reduced levels of GFAP and increased levels of aggregated nuclear protein Lamin A/C in rat brain cortex post-chronic liver failure. We also found increased levels of GMF and inflammatory factors (MMP-3, COX2, CXCL1, and PGE2) in astrocytes post-ammonia treatment in vitro. Additionally, pharmacological inhibition of upstream signaling of GMF (ONS, JNK1/2, and cMyc) or GMF inhibitors W-7 and trifluoperazine significantly reduced the levels of inflammatory factors, the number of AT2A cells, as well as the cognitive and motor deficits in TAA-treated rats. Increased levels of GMF were also identified in human post-mortem brain sections. These findings strongly suggest that increased levels of astrocytic GMF due to elevated levels of ONS, JNK1/2, and cMyc and the subsequent inflammation contribute to the development of AT2A and the consequent cognitive, and motor deficits in chronic liver failure.

8418 Association of GLP-1 Receptor Agonists and SGLT-2 Inhibitors with Major Adverse Cardiovascular Events and Serious Liver Events among Patients with Type 2 Diabetes and MASLD

Abstract Disclosure: A. Kutz: None. D.J. Wexler: None. J. Liu: None. J.M. Paik: None. E. Patorno: None. Introduction and study question Little is known about the cardiovascular (CV) and hepatic effectiveness of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium–glucose cotransporter 2 inhibitors (SGLT-2i) in people with type 2 diabetes (T2D) and known metabolic dysfunction-associated steatotic liver disease (MASLD) in clinical practice. We assessed the comparative CV and hepatic effectiveness and the safety of GLP-1 RA and SGLT-2i in people with T2D and prevalent MASLD. Methodology Using pooled data from Medicare fee-for-service (2013–2020) and a large U.S. health insurance database (2013-June 2022), we conducted two propensity-score fine stratification weighted cohort studies including adults with T2D and a diagnosis of MASLD who initiated GLP-1RA, SGLT-2i, or dipeptidyl peptidase 4 inhibitors (DPP-4i, reference). Using Cox proportional hazards models, we assessed the primary CV effectiveness composite outcome of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, or all-cause mortality. The primary hepatic effectiveness outcome was a composite of serious liver events (hospitalization for ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, bleeding esophageal varices, hepatic encephalopathy, or liver transplantation). The safety outcome was a composite of severe adverse events (lower limb amputation, non-vertebral fracture, emergency admission for hypoglycemia, or hospitalization for acute kidney injury, diabetic ketoacidosis [DKA], severe genital or urinary tract infection, acute pancreatitis, or biliary event). Major results Compared with DPP-4i (n=17,084 initiators), the hazard ratio (HR) for the primary CV outcome associated with GLP-1 RA (n=13,666 initiators) was 0.67 (95% CI, 0.56 to 0.81), corresponding to an incidence rate difference (IRD) per 1,000 person-years of -21.6 (95% CI, -26.7 to -16.6). The HR for the primary hepatic outcome was 0.47 (95% CI, 0.25 to 0.90), the IRD -2.1 (95% CI -3.4 to -0.9). Similar CV benefits were observed for SGLT-2i (n=11,108) vs DPP-4i (n=16,979), with a HR for the primary CV outcome of 0.82 (95% CI 0.70–0.96) and an IRD of -11.0 (95% CI -16.2 to -5.8). For the primary hepatic outcome, the HR was 0.81 (95% CI 0.45 to 1.44) and the IRD -1.1 (95% CI -2.4 to 0.3). Severe adverse events were not more frequent with GLP-1RA or SGLT-2i compared with DPP-4i. Interpretation and conclusion Among people with T2D and MASLD, the use of GLP-1 RA or SGLT-2i was associated with fewer CV events, vs DPP-4i, while GLP-1 RA also reduced serious liver events. Compared with DPP-4i, GLP-1RA or SGLT-2i were not associated with higher safety adverse event rates. Presentation: 6/2/2024

Immediate and Long-Term Results of Portacaval Shunt Surgeries in Portal Hypertension: 10-Year Clinical Experience of a Regional Vascular Surgery Department

INTRODUCTION: The number of patients with liver cirrhosis (LC) makes 20–40 cases per 100 thousand populations and rises steadily. A five-year survival rate of patients with LC in the compensation stage is 50%–62%, in the decompensation stage — 11%–40%. In the overwhelming majority of patients (80%–90%), LC leads to the compensatory formation of esophageal and gastric varices (EV and GV, respectively), which is further complicated with a life-threatening bleeding in 30% of patients. AIM: To evaluate 5-year results of partial portacaval shunt surgeries. MATERIALS AND METHODS: The paper describes a 10-year clinical experience of the vascular surgery department of Yaroslavl Regional Clinical Hospital in surgical treatment of patients with LC with a clinical presentation of portal hypertension, with recorded esophageal and gastric variceal bleeding. The study included 26 patients (of them 11 men; the mean age 48 ± 7.3 years) with LC (A and B classes on Child-Pugh scale), who underwent planned reconstructive surgery on the portal system. By the type of anastomosis, the patients were divided into 3 groups: group 1 — mesocaval anastomosis (n = 6); group 2 — distal splenorenal anastomosis with preservation of spleen (n = 10); group 3 — splenorenal H-shaped shunt. The primary end points of the study were survival of the patients, rebleeding from EV, shunt patency. Secondary end points were dynamics of EV size, changes in the spleen size, dynamics of the portal and splenic veins size, blood flow directions in the portal system, the presence of hepatic encephalopathy. Postoperative mortality was 3.8%. RESULTS: Survival at 1, 3 and 5 years was 96%, 90% and 58, respectively, and patency of anastomoses was 96%, 96% and 91%, respectively. Rebleeding at 1 year made 4% (n = 1), at 3 years — 0, at 5 years — 17% (n = 2). Changes in the hemodynamics of the portal system were recorded after formation of all types of anastomoses: reduction of the diameter of the portal vein by on average 5 mm, of the splenic vein by 3 mm, of the spleen size by 210 cm3. Shunt thrombosis occurred in two of 26 patients (7.7%) at 1 year (splenorenal H-shaped shunt with use of prosthesis) and 4 years (splenorenal autovenous shunt), respectively. CONCLUSION: The formation of partial portacaval anastomoses in patients with portal hypertension and episodes of bleeding from esophageal varices is a reliable prevention of rebleeding. The first bleeding episode is an indication for an open surgery in case the transjugular intrahepatic stenting is impossible. Survival rate of patients after portacaval shunt surgeries is determined by the initial degree of hepatic failure and patency of the formed anastomoses.